ACS Publications. Most Trusted. Most Cited. Most Read
A Cancer Nanovaccine for Co-Delivery of Peptide Neoantigens and Optimized Combinations of STING and TLR4 Agonists
More

OR SEARCH CITATIONS

My Activity
Publications

Figure 1Loading Img
Download Hi-Res ImageDownload to MS-PowerPointCite This:ACS Nano 2024, 18, 9, 6845-6862
  • Open Access
Article

A Cancer Nanovaccine for Co-Delivery of Peptide Neoantigens and Optimized Combinations of STING and TLR4 Agonists
Click to copy article linkArticle link copied!

  • Jessalyn J. Baljon
    Jessalyn J. Baljon
    Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    More by Jessalyn J. Baljon
  • Alexander J. Kwiatkowski
    Alexander J. Kwiatkowski
    Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    More by Alexander J. Kwiatkowski
  • Hayden M. Pagendarm
    Hayden M. Pagendarm
    Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    More by Hayden M. Pagendarm
    Orcidhttps://orcid.org/0000-0001-7611-6120
  • Payton T. Stone
    Payton T. Stone
    Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    More by Payton T. Stone
  • Amrendra Kumar
    Amrendra Kumar
    Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    More by Amrendra Kumar
  • Vijaya Bharti
    Vijaya Bharti
    Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    More by Vijaya Bharti
  • Jacob A. Schulman
    Jacob A. Schulman
    Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    More by Jacob A. Schulman
  • Kyle W. Becker
    Kyle W. Becker
    Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    More by Kyle W. Becker
    Orcidhttps://orcid.org/0000-0003-1627-2724
  • Eric W. Roth
    Eric W. Roth
    Northwestern University Atomic and Nanoscale Characterization Experimental (NUANCE) Center, Northwestern University, Evanston, Illinois 60208, United States
    More by Eric W. Roth
  • Plamen P. Christov
    Plamen P. Christov
    Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    More by Plamen P. Christov
  • Sebastian Joyce
    Sebastian Joyce
    Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    Department of Veteran Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States
    Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    More by Sebastian Joyce
  • John T. Wilson*
    John T. Wilson
    Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    *Email: [email protected]
    More by John T. Wilson
    Orcidhttps://orcid.org/0000-0002-9144-2634
Open PDFSupporting Information (1)

ACS Nano

Cite this: ACS Nano 2024, 18, 9, 6845–6862
Click to copy citationCitation copied!
https://doi.org/10.1021/acsnano.3c04471
Published February 22, 2024

Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Abstract

Click to copy section linkSection link copied!
High Resolution Image
Download MS PowerPoint Slide

Immune checkpoint blockade (ICB) has revolutionized cancer treatment and led to complete and durable responses, but only for a minority of patients. Resistance to ICB can largely be attributed to insufficient number and/or function of antitumor CD8+ T cells in the tumor microenvironment. Neoantigen targeted cancer vaccines can activate and expand the antitumor T cell repertoire, but historically, clinical responses have been poor because immunity against peptide antigens is typically weak, resulting in insufficient activation of CD8+ cytotoxic T cells. Herein, we describe a nanoparticle vaccine platform that can overcome these barriers in several ways. First, the vaccine can be reproducibly formulated using a scalable confined impingement jet mixing method to coload a variety of physicochemically diverse peptide antigens and multiple vaccine adjuvants into pH-responsive, vesicular nanoparticles that are monodisperse and less than 100 nm in diameter. Using this approach, we encapsulated synergistically acting adjuvants, cGAMP and monophosphoryl lipid A (MPLA), into the nanocarrier to induce a robust and tailored innate immune response that increased peptide antigen immunogenicity. We found that incorporating both adjuvants into the nanovaccine synergistically enhanced expression of dendritic cell costimulatory markers, pro-inflammatory cytokine secretion, and peptide antigen cross-presentation. Additionally, the nanoparticle delivery increased lymph node accumulation and uptake of peptide antigen by dendritic cells in the draining lymph node. Consequently, nanoparticle codelivery of peptide antigen, cGAMP, and MPLA enhanced the antigen-specific CD8+ T cell response and delayed tumor growth in several mouse models. Finally, the nanoparticle platform improved the efficacy of ICB immunotherapy in a murine colon carcinoma model. This work establishes a versatile nanoparticle vaccine platform for codelivery of peptide neoantigens and synergistic adjuvants to enhance responses to cancer vaccines.

This publication is licensed under

CC-BY 4.0 .
  • cc licence
  • by licence
Copyright © 2024 The Authors. Published by American Chemical Society

Subjects

what are subjects

Keywords

what are keywords
Immune checkpoint blockade (ICB) has transformed immunotherapy for a wide variety of cancers, resulting in long-term and durable responses for a subset of patients. (1) However, many, if not most, patients do not respond to currently approved ICB antibodies for a multitude of reasons, including a low endogenous T cell response to tumor antigens and/or an insufficient number of tumor antigen-specific CD8+ T cells that infiltrate into solid tumors. (2−4) A promising strategy to increase the efficacy of ICB therapy is to employ therapeutic cancer vaccines to prime and/or expand tumor-specific CD8+ T cells that can be reactivated in response to ICB. (5−9) However, cancer vaccines have typically demonstrated a limited capacity to generate antigen-specific T cell responses in patients, historically leading to poor therapeutic outcomes in the clinic. (10−12) The recent discovery of peptide neoantigens─antigens that arise from mutations in cancer cells─has revitalized interest in therapeutic cancer vaccines. Since neoantigens are only expressed on cancer cells, immunization can lead to a more potent effector T cell response with a significantly reduced risk of autoimmune responses against self-antigen. (13) As such, neoantigen peptide-based cancer vaccines have been tested in a number of clinical trials. (6,10,12) In these trials, biopsies of the patient’s tumor and nonmalignant tissue are subjected to whole-exome sequencing to find mutated genes in the tumor. Human leukocyte antigen typing is then required to determine which mutations result in the presentation of potentially immunogenic epitopes. Major histocompatibility complex class I (MHC-I) epitopes are predicted computationally, and these peptides are then synthesized and injected into a patient in a vaccine formulation. In several of the cancer vaccine trials, vaccination induced a detectable antigen-specific T cell response; however, very few have had meaningful clinical benefit. (14) This could in part be due to the fact that peptide-based vaccines often suffer from weak immunogenicity, leading to poor effector T cell responses. The poor immunogenicity of peptide antigens can be attributed to several intertwined pharmacological barriers, including rapid clearance, poor uptake by dendritic cells (DCs), low accumulation in secondary lymphoid organs (i.e., lymph nodes), inefficient cross-presentation on MHC-I, and potentially, inappropriate choice of immunostimulatory adjuvant(s). (15−18)
Adjuvants are essential to enhancing immune responses to peptide antigens. Adjuvants are included in cancer vaccines to stimulate the innate immune system to induce costimulatory molecule expression on dendritic cells and pro-inflammatory cytokine secretion, which enhance priming and activation of antigen-specific CD8+ T cells. (19−21) While early cancer vaccine clinical trials used adjuvants approved for use in infectious disease vaccines that elicit humoral responses (e.g., MF59), it is now recognized that such adjuvants tend to result in poor cellular immunity, prompting more recent use of agonists of pattern recognition receptors (PRRs) such as CpG DNA (TLR9), monophosphoryl lipid A (MPLA; TLR4), and imiquimod (TLR7). (22−24) Notably, recent neoantigen clinical trials have used a soluble mixture of a pool of peptide neoantigens and the adjuvant poly-ICLC, a polycation/nucleic acid polyplex that activates TLR3 and MDA-5. (25,26) Such phase-I trials provide promising proof-of-concept for neoantigen-targeted vaccines. Nonetheless, they yield only suboptimal CD8+ T cell responses against a fraction of the antigenic targets with minimal evidence of therapeutic efficacy. (12) This may, in part, be related to suboptimal vaccine formulation as we, and others, have demonstrated that copackaging of antigen and adjuvant into a common carrier enhances cellular immune responses to vaccines. (27−35) Collectively, these challenges in antigen and adjuvant delivery motivate the development and optimization of cancer vaccines to augment CD8+ T cell responses to peptide neoantigens.
To address this unmet need, we and others have turned to pathogens for inspiration in vaccine design. (36,37) For example, we recently evaluated codelivery of peptide antigens and the stimulator of interferon genes (STING) agonist cGAMP, an adjuvant that induces a type I interferon (IFN-I) response and has been shown to enhance the antigen-specific CD8+ T cell response. (38−41) We showed that dual-delivery of peptide antigen and cGAMP in endosomolytic polymer vesicles (polymersomes) can induce a robust cytotoxic CD8+ T cell response. (33) The polymersomes were assembled using poly[(ethylene glycol)-block-[(2-diethylaminoethyl methacrylate)-co-(butyl methacrylate)-co-(pyridyl disulfide ethyl methacrylate)]] (PEG-DBP) diblock copolymers. Akin to viruses that escape endo/lysosomal degradation, protonation of diethylaminoethyl methacrylate (DEAEMA) groups in acidic endosomes results in nanoparticle disassembly and exposure of cationic DEAEMA and hydrophobic butyl methacrylate (BMA) residues that act cooperatively to destabilize the endosomal membrane and release associated drug cargo to the cytosol. This approach dramatically enhances the immunostimulatory potency of cGAMP, an anionic molecule that is limited by poor cellular uptake and inefficient cytosolic delivery, while also promoting delivery of peptide antigens to the cytosol to promote cross-presentation on MHC-I molecules, which is critical to activate a CD8+ T cell response. (42)
When infected with a pathogen, multiple PRR pathways are typically activated to produce a broader and more robust innate immune response and modulate the downstream adaptive immune response, but most cancer vaccines typically only include a single adjuvant. (43) Therefore, in recent years several groups have begun to explore the use of multiple, potentially synergistic, adjuvants in a single vaccine platform to enhance and/or tune the innate immune response and further improve antigen immunogenicity and vaccine efficacy. (44−52) Notably, several studies have shown that using STING agonists in combination with other PRR agonists can further augment the innate immune response with potential to enhance response to vaccines. (44−49,53−59) For example, previous studies have shown that STING agonists used in combination with TLR4 agonists can enhance the IFN-I response, potentially due to amplification of downstream NF-κB and interferon regulatory factor 3 (IRF3) pathways. (53,54,56) Atukorale et al. found that coencapsulation of a STING agonist, cdGMP, and MPLA in liposomes enhanced IFN-β production and improved therapeutic efficacy in a B16.F10 melanoma model. (54) Additionally, Hanson et al. found that when they adjuvanted a liposomal-based vaccine with both cdGMP and MPLA it resulted in an enhanced IgG antibody titer. (53) Therefore, we hypothesized that coordinated codelivery of a STING (cGAMP) and TLR4 (MPLA) agonist could act synergistically to enhance dendritic cell activation and antigen cross-presentation, resulting in a more robust antitumor T cell response and improved vaccine efficacy.
To explore this, we leveraged endosomolytic polymersomes previously investigated in our group, (60) which provide an ideal carrier to copackage STING and TLR4 agonists in a defined manner: the vesicular structure allows amphiphilic MPLA to be inserted into the polymeric bilayer at high efficiency for surface display and activation of TLR4, while cGAMP in the aqueous core is released cytosolically to activate STING (Figure 1A). We found that confined impingement jet (CIJ) mixing results in highly uniform polymersomes and efficiently coloads peptide antigen, cGAMP, and MPLA at defined ratios. Co-delivery of the antigen and adjuvants using this endosomolytic nanoparticle platform resulted in an increased IFN-I response, activation of dendritic cells, antigen cross-presentation, and generation of antigen-specific CD8+ T cells that increased response to anti-PD-1 ICB.

Figure 1

Figure 1. Fabrication and characterization of nanoparticle platform. (A) Schematic representation of coloaded nanoparticle vaccine platform promoting MPLA delivery to cell surface and endosome, and cGAMP and peptide antigen delivery to cytosol via endosomal escape. This enhances innate immune signaling for dendritic cell activation and antigen presentation on MHC-I, which together activate a CD8+ T cell response. Made with BioRender.com. (B) Chemical composition and structure of mPEG-block-(DEAEMA-co-BMA) diblock copolymer. (C) Schematic representation of formulation of nanoparticle via confined impingement jet mixing. Made with BioRender.com. (D) Representative cryogenic electron micrograph of nanoparticle coloaded with antigen, cGAMP, and MPLA. (E) Representative size distribution of empty nanoparticle and nanoparticle coloaded with antigen, cGAMP, and MPLA as measured by dynamic light scattering. (F) Representative fluorescent images of NCI H358 cells expressing a Gal9-mCherry fusion protein after treatment with PBS or the loaded nanoparticle (NP). (G) Vesicle count per cell for NCI H358 cells expressing a Gal9-mCherry fusion protein after treatment with indicated formulations (mean ± SD; n = 3–11 biologically independent samples, **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (H) In vitro evaluation of IRF3 and NF-κB activation after treatment with indicated formulation for 24 h (mean ± SD; n = 3 biologically independent samples).

High Resolution Image
Download MS PowerPoint Slide

Results and Discussion

Click to copy section linkSection link copied!

Formulation of Nanoparticle Vaccine via Confined Impingement Jet Mixing

We first synthesized the pH-responsive diblock copolymer poly[(ethylene glycol)-block-[(2-diethylaminoethyl methacrylate)-co-(butyl methacrylate)]] (PEG-DB) via reversible addition–fragmentation chain transfer (RAFT) polymerization. The first block is composed of a 2 kDa polyethylene glycol (PEG) chain to impart hydrophilicity and colloidal stability. The second block is a 12 kDa random copolymer composed of DEAEMA and BMA at a 60:40 molar ratio, respectively (Figure 1B, Table S1). At neutral pH, this block is hydrophobic which allows for diblock copolymer self-assembly into vesicular nanoparticles with a hydrophobic bilayer. Additionally, this ratio of DEAEMA to BMA has been previously shown to be optimal for promoting pH-responsive, endosomal escape. (61) PEG-DB copolymers were self-assembled into vesicular nanoparticles via confined impingement jet (CIJ) mixing (Figure 1C). CIJ mixing utilizes multistream mixers where a diblock copolymer and hydrophobic drug(s) are dissolved in a water miscible organic phase and impinged against an aqueous solution containing hydrophilic drug(s) under turbulent conditions followed by dilution into an aqueous reservoir. The turbulent mixing induces supersaturation and phase separation of copolymer blocks into stable nanoparticles within milliseconds. (62−64) This technique allows for rapid, scalable formation of monodisperse nanoparticles. While CIJ mixing was done manually with 1 mL syringes throughout our studies, this is a scalable process for nanoparticle fabrication; notably, current COVID-19 mRNA-LNP vaccines from Pfizer are formulated using variations of impingement jet mixing at industrial scales. (65,66)
An important benefit to CIJ mixing is that it allows for simultaneous encapsulation of both hydrophilic and hydrophobic drugs. Since neoantigens are patient-specific, they will vary in charge and hydrophobicity and so it is important that a translatable vaccine platform can efficiently load a large variety of peptides. Peptide antigens, varying in length from 15 to 26 amino acids, were dissolved in the aqueous stream resulting in encapsulation efficiencies ranging from 25 to 70% (Table S2). To further optimize peptide loading efficiency, it is possible that in the future peptide properties can be “normalized” to achieve equal and efficient loading of any desired peptide sequence; for example, by adding a sequence of charged or hydrophobic amino acids proximal to the epitope. cGAMP was added to the aqueous stream and had an encapsulation efficiency of 30–40%, and MPLA was added to the organic stream with an encapsulation efficiency of 90–100%.
Through cryoTEM imaging and dynamic light scattering (DLS), we found that this formulation method formed vesicular nanoparticles that were consistently 70–90 nm in diameter with a low polydispersity index (PDI) of 0.1–0.2 (Figure 1D, E). These are ideal physical properties for vaccine delivery as they enable lymphatic drainage and lymph node accumulation after injection, and uptake by professional antigen presenting cells, such as dendritic cells and macrophages. (67,68) Importantly, encapsulation of peptides and adjuvants did not affect the nanoparticle size or polydispersity (Figure 1E, Figure S1). This is a major improvement from the first-generation nanovaccine platform from our group, nanoSTING-vax. (33) This original platform was formulated using a modified direct rehydration method which resulted in nanoparticles ∼200 nm in diameter with a PDI of 0.2–0.3. Additionally, encapsulation of different neoantigen peptides resulted in variation in nanoparticle size and polydispersity.
We also evaluated the ability of the nanoparticle to disrupt the endosomal membrane using a Gal9-mCherry reporter assay. (69) Gal9-mCherry is a fusion protein of Galectin 9 (Gal9), a protein that binds glycans, and the fluorescent mCherry protein. When the endosome of a cell is disrupted, Gal9-mCherry redistributes from the cytosol to the ruptured endosomes, where it binds the newly exposed glycans. Following treatment with an endosomolytic agent, the number of mCherry puncta can be counted as a measurement of disrupted endosomes and a metric of endosomal escape. We used a Gal9-mCherry expressing H358 non-small cell lung cancer cell line and found that nanoparticle formulation significantly enhanced endosomal disruption compared to PBS (Figure 1F, G). Importantly, loading the nanoparticle with peptide and adjuvants did not affect these endosomal escape capabilities. Overall, we demonstrated here that CIJ mixing can be used to reproducibly encapsulate a variety of antigens and adjuvants in vesicular nanoparticles, and these nanoparticles have physicochemical properties (e.g., < 100 nm diameter, low polydispersity) and endosomal disruption capabilities that are ideal for vaccine delivery.
We then tested the innate immune activity of encapsulated cGAMP (NP-cGAMP) and MPLA (NP-MPLA) (Figure 1H). Since activation of the STING pathway requires delivery of cGAMP to the cytosol, where STING is located, we would expect that nanoparticle delivery of cGAMP would enhance its immunostimulatory activity due to the pH-responsive behavior of the polymer. Consistent with our previous work, (70) we found that NP-cGAMP significantly enhanced the IFN-I response compared to free cGAMP. TLR4 is localized on the cell surface and/or within endosomes and therefore MPLA does not require cytosolic delivery. Consistent with this notion, we found that loading in the nanoparticle did not affect NP-MPLA’s activity when compared to free MPLA. Overall, the data indicate that pH-responsive polymersomes offer a promising platform to encapsulate cGAMP and MPLA and motivates evaluation of their capacity to synergistically activate innate immunity to enhance peptide immunogenicity in vivo.

Co-Delivery of cGAMP and MPLA Enhances Co-Stimulatory Molecule Expression and Pro-Inflammatory Cytokine Secretion

Since cGAMP and MPLA activate distinct downstream innate immune pathways, we hypothesized that using them in combination could synergistically enhance the dendritic cell activation needed to initiate a robust CD8+ T cell response. We first tested nanoparticle encapsulated adjuvants (NP-cGAMP and NP-MPLA) separately to assess synergistic potential prior to coloading them into the same particle. We initially evaluated innate immune responses in RAW-Dual reporter cells, a murine macrophage-like cell line that stably expresses reporter genes for Lucia luciferase and secreted embryonic alkaline phosphatase (SEAP) for quantification of IRF and NF-κB pathway activation, respectively. Comparing NP-cGAMP and NP-MPLA alone to mixtures of NP-cGAMP and NP-MPLA at cGAMP:MPLA molar ratios ranging from 1:16 to 16:1, we showed that addition of NP-MPLA significantly enhanced the IFN-I response over that stimulated by NP-cGAMP alone (Figure 2A), and that the addition of NP-cGAMP slightly enhanced the NF-κB activation over that induced by NP-MPLA alone (Figure 2B). Notably, NP-cGAMP and NP-MPLA alone induced a minimal NF-κB response and IFN-I response, respectively, over the concentration range tested here. These findings further motivated us to leverage adjuvant combinations to shape the innate immune response.

Figure 2

Figure 2. Combining NP-cGAMP and NP-MPLA enhances innate immune activation, co-stimulatory molecule expression, and pro-inflammatory cytokine secretion in vitro. (A) In vitro evaluation of interferon activation in RAW-Dual reporter cells after treatment with indicated formulation for 24 h, cGAMP doses indicated on x-axis, MPLA dose for NP-MPLA dose matched to MPLA dose in cGAMP:MPLA 1:16 (mean ± SD; n = 3 biologically independent samples). (B) In vitro evaluation of NF-κB activation in RAW-Dual reporter cells after treatment with indicated formulation for 24 h, MPLA doses indicated on x-axis, cGAMP dose for NP-cGAMP dose matched to cGAMP dose in cGAMP:MPLA 16:1 (mean ± SD; n = 3 biologically independent samples). (C) Flow cytometric quantification of mean fluorescence intensity (MFI) of CD86 expression by BMDCs treated with indicated doses of NP-cGAMP, NP-MPLA, or a mixture of both NPs (n = 3 biologically independent samples). (D–G) Concentration of secreted IFN-β (D), IL-6 (E), TNF-α (F), and IL-1α (G) by BMDCs after treatment with indicated doses of NP-cGAMP, NP-MPLA, or a mixture of both NPs (n = 3 biologically independent samples).

High Resolution Image
Download MS PowerPoint Slide
As an important role of adjuvants is to stimulate costimulatory molecule expression and pro-inflammatory cytokine secretion by DCs, we investigated synergy between cGAMP and MPLA in this context. We treated bone marrow-derived dendritic cells (BMDCs) with NP-cGAMP and NP-MPLA at doses ranging from 0 to 20 μM, and mixtures of both nanoparticles at every dose combination within this matrix. We measured the expression of the costimulatory marker CD86 via flow cytometry and found that multiple dose combinations upregulated CD86 expression (Figure 2C, Figure S2A). In previous work using multiple adjuvants there has been limited evaluation of whether two adjuvants are truly synergistic as defined by a mathematical framework, so we applied the Loewe additivity model to determine if the combinations were synergistic, additive, or antagonistic. This model calculates whether the interaction between two different drugs produces a stronger effect than the expected result if both drugs are the same. (71) A synergy score below −10 is likely to be antagonistic, a score between −10 and 10 is likely to be additive, and a score above 10 is likely to be synergistic. It should be noted that current mathematical models for synergy, including the Loewe model, were originally developed for models of inhibition and cytotoxicity, rather than the activation markers often associated with adjuvant activity; however, using the Loewe model gives an initial indication of the most potent combinations. Calculating the Loewe synergy scores, we found that every combination for CD86 was either additive or synergistic (Figure S3A).
We also measured pro-inflammatory cytokine secretion from BMDCs, specifically screening for IFN-β, IL-6, TNF-α, and IL-1α (Figure 2D–G, Figure S2B–E). We found that secretion of several of these key pro-inflammatory cytokines was enhanced when treated with both adjuvants. The most striking result was with IFN-β, where NP-MPLA produced no effect on its own, but significantly augmented the IFN-β production stimulated by NP-cGAMP. When the Loewe model was applied to these results, most of the cytokines showed additive and synergistic effects (Figure S3B-E). Surprisingly, secretion of TNF-α appeared to be antagonistic at higher concentrations, which we suspect may be related to its cytotoxicity/apoptotic functions at higher doses since even NP-MPLA alone produced a bell-shaped dose–response curve. Overall, these results indicate that cGAMP and MPLA synergistically enhance several innate immune markers that prognosticate a better antigen-specific CD8+ T cell response.
Having found that cGAMP and MPLA synergistically enhance BMDC activation when dosed with separate nanoparticles, we wanted to ensure cGAMP and MPLA could be coloaded into the same nanoparticle and that these synergistic effects were maintained. Previous work using multiple adjuvants has rarely focused on the effect of adjuvant ratio, which has been demonstrated to be an important parameter for synergistic delivery of other classes of drugs (e.g., chemotherapeutics). Based on data with separately loaded adjuvants, we chose to move forward with 3 cGAMP:MPLA molar ratios: 1:4, 1:1, and 4:1. We chose these ratios as there was evidence of synergy at these ratios for expression of CD86 and secretion of key pro-inflammatory cytokines. We were able to coload these adjuvants at the selected three ratios into the nanoparticle platform (NP-cGAMP/MPLA) without affecting particle size, polydispersity, and adjuvant encapsulation efficiency (Figure S4). Next, we found that NP-cGAMP/MPLA significantly enhanced activation of the IFN-I and NF-κB pathways in RAW Dual cells, as compared to NP-cGAMP and NP-MPLA, with the 1:4 ratio having the strongest effect, followed by the 1:1 ratio (Figure 3A, B).

Figure 3

Figure 3. NP-cGAMP/MPLA enhances innate immune activation, co-stimulatory molecule expression, and pro-inflammatory cytokine secretion in vitro. (A) In vitro evaluation of interferon activation in RAW-Dual reporter cells after treatment with indicated formulation for 24 h, cGAMP doses indicated on x-axis, MPLA dose for NP-MPLA dose matched to MPLA dose in NP-cGAMP/MPLA(1:4) (mean ± SD; n = 3 biologically independent samples). (B) In vitro evaluation of NF-κB activation in RAW-Dual reporter cells after treatment with indicated formulation for 24 h, MPLA doses indicated on x-axis, cGAMP dose for NP-cGAMP dose matched to cGAMP dose in NP-cGAMP/MPLA(4:1) (mean ± SD; n = 3 biologically independent samples). (C) Flow cytometric quantification of mean fluorescence intensity (MFI) of CD86 expression by BMDCs treated with indicated doses of NP-cGAMP, NP-MPLA, or NP-cGAMP/MPLA (n = 3 biologically independent samples). (D–G) Concentration of secreted (D) IFN-β, (E) IL-6, (F) TNF-α, and (G) IL-1α by BMDCs after treatment with indicated doses of NP-cGAMP, NP-MPLA, or NP-cGAMP/MPLA (n = 3 biologically independent samples).

High Resolution Image
Download MS PowerPoint Slide
Expression of CD86 on BMDCs was also enhanced when treated with NP-cGAMP/MPLA compared to dose-matched NP-cGAMP and NP-MPLA (Figure 3C, S5A). Calculated Loewe synergy scores indicated that the expression of CD86 was a mix of additive and synergistic with many doses at the 1:4 ratio being synergistic (Figure S6A). This indicates that the synergistic effects seen with separately loaded adjuvants were maintained, and in some cases enhanced, with NP-cGAMP/MPLA. It should be noted that treatment with coloaded NP-cGAMP/MPLA significantly lowers the dose of polymer required when compared to mixtures of NP-cGAMP and NP-MPLA, thereby decreasing the potential for adverse or confounding effects related to polymer-mediated toxicity.
Secretion of the same pro-inflammatory cytokines was also measured, which were significantly enhanced when BMDCs were treated with NP-cGAMP/MPLA (Figure 3D–G, S5B–E). Loewe scores showed that NP-cGAMP/MPLA synergistically or additively increased secretion of all cytokines, in a manner that was not strongly ratio dependent (Figure S6B–E). Interestingly, TNF-α was synergistic at doses below 5 μM, most notably at the 1:4 ratio, but was then antagonistic at higher doses for reasons discussed above. Overall, these data indicate that nanoparticles coloaded with cGAMP and MPLA synergistically enhance STING and TLR4 signaling. These findings prompted us to harness the synergistic properties of coloaded nanoparticles to enhance the immunogenicity of peptide antigens, which by themselves are poorly, if at all, immunogenic.

Nanoparticle Delivery Enhances Lymphatic Accumulation and Uptake by Antigen Presenting Cells

As cGAMP and MPLA synergistically enhance the expression of CD86 and the secretion of several pro-inflammatory cytokines including IFN-β and IL-6, we developed a complete nanovaccine formulation that coloaded peptide antigens with cGAMP and MPLA: NP-Pep/cGAMP/MPLA. We were able to coload a synthetic long peptide (SLP) derived from the model antigen ovalbumin (OVA) that contains the immunodominant MHC class I SIINFEKL epitope (OVAp), cGAMP, and MPLA into the nanoparticle at the same 3 cGAMP:MPLA molar ratios −1:4, 1:1, 4:1 (Figure S7). This also highlights an important advantage of the CIJ formulation approach and the biphasic structure of the polymersome which together enable coloading of chemically distinct adjuvants (e.g., cGAMP and MPLA) at precisely defined ratios controlled by inlet feed concentrations. Another attractive feature of using a nanoparticle vaccine platform is that nanoparticles smaller than 100 nm in diameter are known to preferentially drain to lymph nodes, where DC and primary T cell activation occurs. (68) To evaluate this, we formulated NP-Pep/cGAMP/MPLA(1:4) using Cy5-labeled OVAp (Cy5-OVAp) to track it is distribution to the lymph node and uptake by immune cells, compared to a soluble mixture of Cy5-OVAp, cGAMP, and MPLA (Pep+cGAMP+MPLA(1:4)). We subcutaneously vaccinated mice, harvested the draining inguinal lymph node 6h later, and used exvivo fluorescence imaging to assess the accumulation of peptide in the lymph node. We found that the nanoparticle vaccine significantly enhanced accumulation of the peptide compared to PBS and the soluble mixture (Figure 4A, B). Importantly, no Cy5-OVAp was detected in the spleen or a nondraining lymph node (Figure S8), suggesting that NPs do not enter the circulation to a detectable level. Additionally, we quantified the uptake of the Cy5-OVAp in immune cell populations─macrophages, DCs, neutrophils, B cells, CD4+ T cells, and CD8+ T cells─and found that the nanoparticle platform significantly enhanced antigen uptake by macrophages and DCs when compared to the soluble mixture (Figure 4C). We then evaluated uptake of the nanoparticle in DC subsets─plasmacytoid DCs (pDCs, BST+CD8–) and conventional DCs, cDC1s (CD8+) and cDC2s (BST–CD8–)─and found that all subsets significantly took up antigen compared to the PBS control, with ∼15% of pDCs and 1–2% of cDCs internalizing the antigen (Figure 4D). Although cDC1s are thought of as the most potent cross-presenting DCs, pDCs are known to be a strong producer of IFN-I, which in turn increases overall antigen cross-presentation and CD8+ T cell priming. (72,73) Overall, this finding indicates that NP-Pep/cGAMP/MPLA can enhance antigen accumulation in the lymph node and uptake by antigen presenting cells, which is needed for priming and activation of antigen-specific CD8+ T cells.

Figure 4

Figure 4. Nanoparticle vaccine enhances lymphatic accumulation and uptake by antigen presenting cells. (A) Fluorescent images of vaccine site draining lymph node 6h after subcutaneous injection of vaccine formulated with Cy5-OVAp. (B) Quantification of fluorescence in vaccine site draining lymph node (mean ± SD; n = 5 mice/group; **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (C) Percentage of Cy5-OVAp positive cells among immune cell populations in vaccine draining lymph node 6h after injection of vaccine formulated with Cy5-OVAp (mean ± SD; n = 5 mice/group; ***P < 0.001; one-way ANOVA with Tukey’s multiple comparisons). (D) Percentage of Cy5-OVAp positive cells among pDCs and cDCs (cDC1 and cDC2) in the vaccine site draining lymph node 6h after injection of vaccine formulated with Cy5-OVAp (mean ± SD; n = 6–8 mice/group; *P < 0.05, **P < 0.01; unpaired t test).

High Resolution Image
Download MS PowerPoint Slide

Nanoparticle Co-Delivery of Antigen, cGAMP, and MPLA Enhances Antigen-Specific CD8+ T Cell Response

Next, we evaluated whether the complete vaccine formulation (NP-Pep/cGAMP/MPLA) activates dendritic cells by measuring the expression of CD86 on BMDCs after treatment. We compared NP-Pep/cGAMP/MPLA at each cGAMP:MPLA molar ratio (1:4, 1:1, 4:1) to NP-Pep/cGAMP and NP-Pep/MPLA. We found that NP-Pep/cGAMP/MPLA(1:4) significantly enhanced expression of CD86 when compared to NP-Pep/MPLA (Figure 5A). For all the treatment groups the dose of MPLA was maintained, and the dose of cGAMP was adjusted depending on the cGAMP:MPLA ratio. The cGAMP dose for NP-Pep/cGAMP was dose-matched to NP-Pep/cGAMP/MPLA(4:1) and was 16-fold higher than the cGAMP dose for NP-Pep/cGAMP/MPLA(1:4). So, it is unsurprising that NP-Pep/cGAMP/MPLA(1:4) did not significantly enhance expression compared to NP-Pep/cGAMP, and it is notable that it even induced similar expression levels. Additionally, we confirmed that formulations with MPLA, compared to NP-Pep/cGAMP, do not significantly enhance uptake by DCs which could occur via binding of MPLA in the bilayer to TLR4 on the cell surface (Figure S9).

Figure 5

Figure 5. Nanoparticle vaccine enhances dendritic cell activation and cross-presentation, activates antigen-specific CD8+ T cells, and provides therapeutic efficacy in the EG7.OVA model. (A) Flow cytometric quantification of mean fluorescence intensity (MFI) of CD86 expression by BMDCs treated with indicated formulations (mean ± SD; n = 2; **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (B) Flow cytometric quantification of mean fluorescence intensity (MFI) or percentage of SIINFEKL-H2Kb positive BMDCs treated with indicated formulations and stained with PE-labeled antibody against SIINFEKL/H-2Kb (mean ± SD; n = 3; ****P < 0.0001; one-way ANOVA with Tukey’s multiple comparisons). (C) Vaccination and downstream analysis scheme. (D) Quantification of the frequency of SIINFEKL-specific CD8+ T cells in spleen after vaccination using peptide/MHC tetramer staining (mean ± SD; n = 10 mice/group; ****P < 0.0001; one-way ANOVA with Tukey’s multiple comparisons). (E) Quantification of the frequency of SIINFEKL-specific CD8+ T cells in spleen after vaccination using peptide/MHC tetramer staining comparing wild-type mice to Batf3–/– mice (mean ± SD; n = 5–8 mice/group; ***P < 0.001, ****P < 0.0001; two-way ANOVA with Tukey’s multiple comparisons). (F) Tumor challenge and therapeutic vaccination scheme. (G) Average EG7.OVA tumor growth in response to indicated formulation (mean ± SEM; n = 8–10 mice/group). (H) Average tumor volume on day 20 after tumor inoculation (mean ± SEM; n = 8–10 mice/group; **P < 0.01, ***P < 0.001; one-way ANOVA with Tukey’s multiple comparisons). (I) Kaplan–Meier survival curve using 2000 mm3 tumor volume as the end point (n = 8–10 mice/group; statistical significance between indicated treatment versus PBS and NP-Pep/cGAMP; *P < 0.05, **P < 0.01; Mantel–Cox log-rank test). (J) Representative flow cytometry plots and quantification of IFNγ+TNFα+ CD8+ T cells after ex vivo restimulation of splenocytes with SIINFEKL peptide (mean ± SD; n = 8 mice/group; ****P < 0.0001; unpaired t test). (K) Percentage of central and effector memory antigen-specific CD8+ T cells (TCM and TEM) in spleen after vaccination (mean ± SD; n = 8 mice/group; ****P < 0.0001; unpaired t test).

High Resolution Image
Download MS PowerPoint Slide
We next tested whether NP-Pep/cGAMP/MPLA enhances antigen cross-presentation on BMDCs. Briefly, we treated BMDCs with free peptide, encapsulated peptide without adjuvants (NP-Pep), NP-Pep/cGAMP, NP-Pep/MPLA, and NP-Pep/cGAMP/MPLA at each cGAMP:MPLA ratio. The presentation of the MHC-I restricted OVA epitope, SIINFEKL, on MHC-I was measured by flow cytometry by using a fluorescently labeled antibody against SIINFEKL bound to H-2Kb (Figure 5B). We found that all NP-Pep/cGAMP/MPLA formulations enhanced cross-presentation as compared to PBS, free Pep, and NP-Pep. The 1:4 ratio of cGAMP:MPLA enhanced cross-presentation the most and was significantly higher than NP-Pep/cGAMP and NP-Pep/MPLA. It is unsurprising that free Pep does induce a measurable amount of antigen cross-presentation, as the SLP used, OVAp, can still be degraded by intra- and extracellular proteases and presented on MHC-I, but less efficiently. (42) Collectively, these data indicate that codelivery of the synergistic adjuvants, cGAMP and MPLA, with peptide neoantigens using a pH-responsive nanoparticle platform can enhance dendritic cell activation and peptide antigen cross-presentation on MHC-I, with the potential to enhance CD8+ T cell responses.
We next evaluated the antigen-specific CD8+ T cell response in vivo. Mice were subcutaneously vaccinated with PBS (vehicle), NP-Pep, NP-Pep/cGAMP, NP-Pep/MPLA, or NP-Pep/cGAMP/MPLA at each ratio on day 0, and then boosted on days 7 and 14 (Figure 5C). On day 21 splenocytes were harvested and the SIINFEKL-specific CD8+ T cell response was quantified by pOVA/H-2Kb tetramer staining (Figure 5D). We found that NP-Pep generated a minimal (∼0.5%) SIINFEKL-specific CD8+ T cell response, with the addition of cGAMP (NP-Pep/cGAMP) and MPLA (NP-Pep/MPLA) generating a stronger response (∼1%). However, copackaging of antigen with both adjuvants (NP-Pep/cGAMP/MPLA) tended to enhance the antigen-specific T cell response (∼5%) at all 3 adjuvant ratios when compared to any of the other formulations.
To evaluate whether cross-presenting DCs were responsible for generating this antigen-specific CD8+ T cell response, we repeated this study using Batf3–/– mice, which lack the cross-presenting CD8α+ DCs. (74) We found that the percentage of SIINFEKL-specific CD8+ T cells was significantly reduced in Batf3–/– mice after vaccination with NP-Pep/cGAMP/MPLA(1:4) compared to wild type mice (Figure 5E). Collectively, these data demonstrate that incorporating both cGAMP and MPLA into the nanovaccine enhances dendritic cell activation and antigen cross-presentation to promote cellular immunity in response to vaccination with peptide antigens.

Nanoparticle Vaccine Inhibits Tumor Growth and Improves Survival in Mice

We then evaluated the ability of the platform to enhance therapeutic cancer vaccine efficacy in vivo using the EG7.OVA model–a murine thymoma EL-4 cell line that expresses the model OVA antigen. Mice were inoculated subcutaneously in the flank with 3 × 105 EG7.OVA cells on day 0, and then vaccinated on days 7, 14, and 21 with PBS, NP-Pep/cGAMP, NP-Pep/MPLA, or NP-Pep/cGAMP/MPLA at each ratio (Figure 5F). Tumor growth and survival were monitored throughout the study (Figure 5G–I, Figure S10). All NP-Pep/cGAMP/MPLA formulations delayed tumor growth to a significantly greater degree than PBS. Additionally, both NP-Pep/cGAMP/MPLA(1:4) and NP-Pep/cGAMP/MPLA(1:1) significantly prolonged survival as compared to mice that received NP-Pep/cGAMP and PBS. Overall, these data indicate that the nanoparticle vaccine formulation containing both MPLA and cGAMP as adjuvants can improve therapeutic efficacy in a murine tumor model.

Nanoparticle Vaccine Enhances Functionality of Antigen-Specific CD8+ T Cell Response

We next evaluated the functionality and phenotype of the antigen-specific T cell response generated by the vaccine platform. Moving forward, we chose to use only NP-Pep/cGAMP/MPLA(1:4), as this adjuvant ratio was found to be superior or nearly equivalent to the 4:1 and 1:1 ratios in previous studies (e.g., tetramer response, survival benefit), while using a smaller total dose of adjuvant. Mice were subcutaneously vaccinated with PBS (vehicle) or NP-Pep/cGAMP/MPLA(1:4) on days 0, 7, and 14 (Figure 5C). On day 21 the splenocytes were harvested for intracellular cytokine staining and memory phenotyping. Vaccination resulted in a significant increase in the percentage of polyfunctional INFγ+TNFα+ CD8+ T cells in response to restimulation of splenocytes with SIINFEKL (Figure 5J). Next, the memory phenotype of the CD8+ T cells in the spleen was evaluated by determining the frequency of central memory T cells (TCM, CD44+CD62L+), a memory CD8+ T cell subset that tends to traffic to secondary lymph node organs and persist after an immune response, and effector memory T cells (TEM, CD44+CD62L–), the memory CD8+ T cell subset that resides in peripheral circulation and tissues and is more cytolytic and able to immediately recognize and kill target cells. (75) We found that the nanovaccine generated a significantly stronger antigen-specific TEM response relative to TCM, with TEM comprising ∼80% of the tetramer-positive CD8+ T cell population (Figure 5K). Overall, this indicates that the vaccine platforms can generate a polyfunctional, antigen-specific TEM response, which is important for killing of cancer cells.

Nanoparticle Vaccine Enhances Neoantigen Vaccine Efficacy and Response to ICB

Based on the data using OVA as a model tumor antigen, we next evaluated the efficacy of the vaccine platform using peptide neoantigens generated from mutations in the MC38 colon cancer cell line. We loaded known and established MC38 neoantigens─Reps1 and Adpgk─into the nanoparticle along with cGAMP and MPLA at a 1:4 ratio. All treatments were a mixture of nanoparticles coloaded with Reps1 and adjuvant(s) and nanoparticles coloaded with Adpgk and adjuvant(s). Mice were inoculated with 1 × 106 MC38 cells, and vaccinated 6 days later, with boosts on days 13 and 20 (Figure 6A). Compared to a soluble mixture of peptides and adjuvants (Pep+cGAMP+MPLA(1:4)) and singly adjuvanted nanoparticle vaccines, we found that only NP-Pep/cGAMP/MPLA(1:4) significantly delayed tumor growth (Figure 6B–D) and improved survival (Figure 6E).

Figure 6

Figure 6. Nanoparticle vaccine provides therapeutic efficacy in MC38 adenocarcinoma model and improves the efficacy of αPD-1 ICB therapy. (A) Tumor challenge and therapeutic vaccination scheme. (B) Spider plots of individual tumor growth curves. (C) Average MC38 tumor growth in response to indicated formulation (mean ± SEM; n = 10 mice/group). (D) Average tumor volume on day 22 after tumor inoculation (mean ± SEM; n = 10 mice/group; *P < 0.05; one-way ANOVA with Tukey’s multiple comparisons). (E) Kaplan–Meier survival curve using 2000 mm3 tumor volume as the end point (n = 10 mice/group; statistical significance between NP-Pep/cGAMP/MPLA(1:4) and all other groups shown; *P < 0.05; Mantel–Cox log-rank test). (F) Tumor challenge, therapeutic vaccination, and αPD-1 treatment scheme. (G) Spider plots of individual tumor growth curves. (H) Average MC38 tumor growth in response to indicated formulation (mean ± SEM; n = 8–10 mice/group). (I) Average tumor volume on days 17–25 after tumor inoculation (mean ± SEM; n = 8–10 mice/group; *P < 0.05, **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (J) Kaplan–Meier survival curve using 2000 mm3 tumor volume as the end point (n = 8–10 mice/group; statistical significance between NP-Pep/cGAMP/MPLA(1:4) + αPD-1 and all other groups shown; *P < 0.05; Mantel–Cox log-rank test).

High Resolution Image
Download MS PowerPoint Slide
Since NP-Pep/cGAMP/MPLA(1:4) enhanced the antigen-specific CD8+ T cell response, we next tested if it could enhance the therapeutic efficacy of ICB. MC38 is known to express PD-L1 but is largely resistant to αPD-1/αPD-L1 therapy. (76) Hence, we chose to test the therapeutic efficacy of NP-Pep/cGAMP/MPLA(1:4) in combination with αPD-1 therapy in this model. Mice were subcutaneously inoculated with MC38, then vaccinated every 7 days starting at day 6. Additionally, αPD-1 was administered intraperitoneally every 3–4 days (Figure 6F). We found that αPD-1 alone provided minimal therapeutic efficacy, but αPD-1 used in combination with NP-Pep/cGAMP/MPLA(1:4) significantly delayed tumor growth and improved survival (Figure 6G–J). Taken together, these data provide evidence that NP-Pep/cGAMP/MPLA(1:4) provides therapeutic efficacy as a monotherapy and also enhances the efficacy of αPD-1 ICB in a murine colon adenocarcinoma model.

Nanoparticle Vaccine Activates a Functional Antigen-Specific CD8+ T Cell Response Against Neoantigens

After determining that the vaccine platform, in combination with αPD-1 ICB provided therapeutic efficacy, we evaluated the CD8+ T cell response and phenotype using the vaccine platform with the MC38 neoantigens. Mice were subcutaneously vaccinated with PBS (vehicle) or NP-Pep/cGAMP/MPLA(1:4) on days 0, 7, and 14, and αPD-1 ICB antibodies were administered very 3–4 days (Figure 7A). On day 21 splenocytes were harvested to evaluate the specificity and functionality of the T cell response. First, the Reps1- and Adpgk-specific CD8+ T cell response was evaluated via tetramer staining (Figure 7B). We found that all groups vaccinated with the nanoparticle platform generated a significant antigen-specific CD8+ T cell response. We next evaluated the memory phenotype of these antigen-specific CD8+ T cells. We found that mice vaccinated with NP-Pep/cGAMP/MPLA(1:4) alone or in combination with αPD-1 induced a stronger Reps1- and Adpgk-specific TEM response than TCM response (Figure 7C). We then investigated the functionality of the T cells via intracellular cytokine staining following antigen restimulation with the Reps1 (AQLANDVVL) or Adpgk (ASMTNMELM) epitope and found that mice treated with NP-Pep/cGAMP/MPLA(1:4) + αPD-1 had significantly enhanced polyfunctional INFγ+TNFα+ CD8+ T cells compared to the PBS control (Figure 7D, E). Finally, we further evaluated the functionality of the T cell response via ELISPOT after restimulation of the splenocytes with either the Reps1 or Adpgk epitope. Again, we found that NP-Pep/cGAMP/MPLA(1:4) significantly enhanced the frequency of IFNγ secreting CD8+ T cells (Figure 7F, G). Overall, these data indicate that vaccine platform activates an antigen-specific and functional CD8+ T cell response for known murine neoantigens.

Figure 7

Figure 7. Nanoparticle vaccine activates antigen-specific and functional CD8+ T cells against MC38 neoantigens. (A) Vaccination and downstream analysis scheme. (B) Quantification of the frequency of Reps1-specific and Adpgk-specific CD8+ T cells in spleen after vaccination using peptide/MHC tetramer staining (mean ± SD; n = 7–8 mice/group; *P < 0.05, **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (C) Percentage of central and effector memory antigen-specific CD8+ T cells in spleen after vaccination (mean ± SD; n = 7–8 mice/group; ****P < 0.0001; two-way ANOVA with Tukey’s multiple comparisons). (D) Representative ICCS flow cytometry plots evaluating the percentage of IFNγ+TNFα+ CD8+ T cells after ex vivo restimulation of splenocytes with Reps1 (AQLANDVVL) or Adpgk (ASMTNMELM) peptides. (E) Quantification of flow cytometry data in D (mean ± SD; n = 7–8 mice/group; *P < 0.05, **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (F) Representative ELISPOT wells after ex vivo restimulation of splenocytes with Reps1 (AQLANDVVL) or Adpgk (ASMTNMELM) peptides. (G) Quantification of images in F to determine the CD8+IFNγ+ T cell response (mean ± SD; n = 7–8 mice/group; *P < 0.05, **P < 0.01, ****P < 0.0001; one-way ANOVA with Tukey’s multiple comparisons).

High Resolution Image
Download MS PowerPoint Slide

Conclusion

Click to copy section linkSection link copied!
Although ICB has revolutionized cancer immunotherapy, the lack of robust and long-term responses in a subset of patients indicates the need for combination therapy to enhance efficacy. It has been shown that increased antigen-specific CD8+ T cell infiltration into tumors is often correlated with improved ICB response rates. This has fueled interest in therapeutic cancer vaccines that can activate an antitumor T cell response, thereby enhancing efficacy of ICB. Here, we describe a nanoparticle vaccine platform rationally designed to enhance the immunogenicity of peptide neoantigens. Nanoparticle cancer vaccines can overcome pharmacological barriers associated with soluble antigen delivery to enhance peptide immunogenicity and improve overall therapeutic efficacy. It is important that these nanoparticle platforms are uniform in size, are amenable to scalable formulation methods, and can incorporate a wide variety of patient-specific neoantigen peptides to improve translatability. We utilized CIJ mixing to formulate pH-responsive vesicular nanoparticles as a versatile nanovaccine platform. Our data show that we can quickly and reproducibly formulate nanoparticles that are monodisperse and less than 100 nm in diameter. Additionally, peptide neoantigens and adjuvants with a range of physical properties can be loaded without impacting nanoparticle properties. Furthermore, by exploring the use of multiple adjuvants, we showed that cGAMP and MPLA can act in synergy to further enhance peptide immunogenicity. Our data demonstrated that cGAMP and MPLA synergistically enhance expression of costimulatory molecules on dendritic cells and secretion of pro-inflammatory cytokines, which are both important for robust priming and activation of T cells. Additionally, we show that the nanoparticle vaccine enhances lymph node accumulation and uptake by antigen presenting cell in the lymph node. Co-loading with peptide neoantigens at 3 defined cGAMP:MPLA ratios─1:4, 1:1, and 4:1─in the nanoparticle platform enhanced cross-presentation of the peptide antigen on MHC-I, which is necessary to induce a CD8+ T cell response. In several therapeutic models, the vaccine was able to delay tumor growth and improve survival. Additionally, it improved the therapeutic efficacy of αPD-1 ICB in an MC38 murine tumor model. An important future direction will be to further improve upon the relatively modest therapeutic efficacy of the vaccine; for example, through optimization of dose and regimen, combination with immunomodulators that reprogram the tumor microenvironment, addition of CD4+ T cell helper epitopes, and/or incorporation of additional neoantigenic peptides. Taken together, this nanoparticle vaccine is a promising and versatile platform for harnessing adjuvant synergy to enhance peptide antigen immunogenicity, thereby improving the therapeutic efficacy of neoantigen-targeted cancer vaccines.

Materials and Methods

Click to copy section linkSection link copied!

Polymer Synthesis and Characterization

4-Cyano-4-(phenylcarbonothioylthio)pentanoic acid (CPADB), N,N′-dicyclohexyl carbodiimide (DCC), 4-(dimethylamino)pyridine (DMAP), butyl methacrylate (BMA), 4,4′-azobis(4-cyanovaleric acid) (V501), poly(ethylene glycol) methyl ether (PEG, MW = 2000 Da), dichloromethane, and 1,4-dioxane were purchased from Sigma-Aldrich. 2-(diethylamino)ethyl methacrylate (DEAEMA) was purchased from TCI chemicals. Methoxyphenol inhibitor was removed from DEAEMA and BMA monomers via gravity filtration through aluminum oxide prior to polymerizations.
Poly[(ethylene glycol)-block-[(2-diethylaminoethyl methacrylate)-co-(butyl methacrylate)]] was synthesized via RAFT polymerization. A 2 kDa PEG-CPADB macro-RAFT chain transfer agent (mCTA) was synthesized as previously described. (70) Briefly, PEG (MW = 2000 Da) was coupled to the chain transfer agent CPADB by mixing with DCC and DMAP at a molar ratio of 1:2.5:3:0.15 in dichloromethane and reacting overnight. Unreacted reagent was removed through gravity filtration, and the resulting product was purified by precipitating in cold diethyl ether five times and then vacuum drying. 1H NMR was used to calculate the degree of labeling. This mCTA was then dissolved with DEAEMA and BMA monomers (at a 60:40 molar ratio) and the initiator V501 in 1,4-dioxane, purged with nitrogen gas for 30 min, and polymerized for 18h at 70 °C. An mCTA:initiator of 5:1 and a weight fraction of monomer and mCTA to dioxane of 0.4 were used. The resulting polymer was then precipitated five times in cold pentane and vacuum-dried. 1H NMR was used to calculate polymer composition, degree of polymerization, and theoretical molecular weight (Figure S11).

Nanoparticle Formulation

2’3 cGAMP was synthesized as previously described. (70) MPLA was purchased from Avanti Polar Lipids. Synthetic long peptides (SLPs) containing the epitopes of known neoantigens were purchased from GenScript. The peptides used in this study include the SLP for Ovalbumin, OVAp (SGLEQLESIINFEKL), the MC38 SLP Reps1 (RVLELFRAAQLANDDVVLQIMELC), and the MC38 SLP Adpgk (GIPVHLELASMTNMELMSSIVHQQVF).
Nanoparticles were formulated using CIJ mixing as previously described. (60,62,63) PEG-DB and MPLA were dissolved in THF and aspirated into a 1 mL polypropylene syringe. Peptide and cGAMP were dissolved in water and aspirated into a separate 1 mL polypropylene syringe. The syringes were then attached to the CIJ unit and impinged against each other by hand into a 20 mL scintillation vial. The total volume impinged was then recollected into both syringes at equal volumes and coimpinged again. This was repeated for a total of five impingements. The final impingement was collected into a 4 mL stirring aqueous reservoir. For all formulations, the concentration of PEG-DB was held constant at 10 mg/mL. For NP-Pep, 500 μg/mL peptide was dissolved in the aqueous phase, for NP-cGAMP 500 μg/mL cGAMP was dissolved in the aqueous phase, and for NP-MPLA 400 μg/mL MPLA was dissolved in the organic phase. For NP-cGAMP/MPLA, cGAMP concentration in the aqueous stream ranged from 200 to 100 μg/mL and MPLA concentration in the organic stream ranged from 100 to 400 μg/mL to ensure the desired cGAMP:MPLA molar ratio was achieved. For all formulations containing peptide antigens, peptide concentration in the aqueous stream was maintained at 500 μg/mL, and cGAMP and MPLA concentrations in their inlet streams were adjusted to achieve the correct ratios.
After the final impingement into the aqueous reservoir, unencapsulated drug was removed via ultracentrifugal filtration through a 50,000 Da MWCO membrane. To quantify peptide and cGAMP loading, an aliquot was removed and diluted in acetonitrile and analyzed via HPLC. OVAp was analyzed using a C18 column (130 Å pore size, 5 μm particle size, 150 × 4 mm inside diameter, ThermoScientific) at 60 °C with a gradient mobile phase from 95% water with 0.1% trifluoroacetic acid (TFA) to 95% acetonitrile with 0.1% TFA over 8 min. Reps1 and Adpgk were analyzed using a Hypersil GOLD C4 column (175 Å pore size, 5 μm particle size, 150 × 4.6 mm inside diameter, ThermoScientific) at 60 °C with a gradient mobile phase from 75% water with 0.1% TFA to 95% acetonitrile with 0.1% TFA over 10 min. cGAMP was analyzed via normal phase HPLC as previously described. (77) Encapsulation of MPLA was measured using mass spectrometry, with an LTQ XL Linear Ion Trap Mass Spectrometer (ThermoScientific) coupled to an AQUITY Ultra Performance LC (UPLC) (Waters). The mass spectrometer was operated in negative ionization mode. An AQUITY UPLC BEH C8 column (130 Å pore size, 1.7 μm particle size, 150 × 2.1 mm inside diameter, Waters) was used for chromatographic separation at 45 °C. The mobile phase consisted of 2 solvents: solvent A of 10 mM NH4OAc in ACN/H2O/MeOH 8/1/1 and solvent B of 10 mM NH4OAc in MeOH/Iso/ACN 2/2/1. An isocratic flow of 30% solvent A and 70% solvent B was run at 0.3 mL/min for 15 min. The m/z of 1745.28 was used to quantify MPLA.
Particle diameter and PDI was measured via dynamic light scattering (DLS) by diluting particles in sterile-filtered PBS and characterizing with a Malvern Zetasizer Ultra. For cryoTEM morphology evaluation, 200 mesh Cu grids with a lacey carbon membrane (EMS Cat# LC200-CU-100) were glow-discharged in a Pelco easiGlow glow discharger (Ted Pella Inc., Redding, CA, USA) using an atmosphere plasma generated at 15 mA for 15 s with a pressure of 0.24 mbar. This treatment created a negative charge on the carbon membrane, allowing aqueous samples to spread evenly over of the grid. Four μL of loaded nanoparticles (1 mg/mL stock) was pipetted onto the grid and blotted for 5 s with a blotting pressure of 1, followed by immediate plunging into liquid ethane within an FEI Vitrobot Mark IV plunge freezing instrument (Thermo Fisher Scientific, Waltham, MA, USA). Grids were then transferred to liquid nitrogen for storage. The plunge-frozen grids were kept vitreous at −180 °C in a Gatan Cryo Transfer Holder model 626.5 (Gatan Inc., Pleasanton, CA, USA) while viewing in a JEOL JEM1230 LaB6 emission TEM (JEOL USA, Inc., Peabody, MA,) at 120 keV. Image data was collected by a Gatan Orius SC1000 CCD camera Model 831 (Gatan Inc., Pleasanton, CA, USA).

Gal9 Recruitment Assay

Gal9 recruitment assays were performed as previously described with minor modifications as follows. (69,78) NCI-H358 cells stably expressing Gal9-mCherry were seeded in 96-well black walled clear bottom plates (Grenier, catalog number 655090) at a density of 7,500 cells/well and allowed to adhere overnight. The following day, cells were treated with nanoparticle formulations at indicated concentrations and incubated for an additional 24 h. Media was then exchanged with 100 μL of imaging media (FluoroBrite DMEM supplemented with 25 mM HEPES, 10% FBS, 1% Pen/Strep, and 4 μM Hoechst 33342). Cells were imaged using an ImageXpress Nano Automated Imaging System (Molecular Devices) with a 20 x Nikon CFI60 series objective, courtesy of the Vanderbilt High Throughput Screening Core. Images were analyzed using the Transfluor Application Module within the MetaXpress Software (Molecular Devices), which blindly counted the integrated pixel intensity of the Gal9 positive spots within each image.

In Vitro Evaluation of Adjuvant Activity

Activation of IRF and NF-κB pathways were measured in RAW-Dual and THP1-Dual cells (Invivogen). RAW-Dual cells were cultured in DMEM supplemented with 2 mM l-Glutamine, 4.5 g/mL d-glucose, 10% fetal bovine serum (FBS), 100 U/mL penicillin/100 μg/mL streptomycin, and 100 μg/mL normocin. Zeocin (200 μg/mL) was added every other passage to maintain selection pressure. THP1-Dual cells were cultured in RPMI supplemented with 2 mM l-glutamine, 25 mM HEPES, 10% FBS, 100 U/mL penicillin/100 μg/mL streptomycin, and 100 μg/mL normocin. Zeocin (100 μg/mL) and blasticidin (10 μg/mL) were added every other passage to maintain selection pressure. RAW-Dual (50,000 cells/well) or THP1-Dual (20,000 cells/well) were plated in 96-well plates and treated the next day with indicated formulations and concentrations for 24 h. Relative IRF activation was measured using QUANTI-Luc, a lucia luciferase detection reagent, and relative NF-κB activation was measured using QUANTI-blue, a secreted alkaline phosphatase (SEAP) detection reagent, by following manufacturer’s instructions.

In Vitro Evaluation of BMDC Activation

BMDCs were prepared from bone marrow cells harvested from the femurs and tibias from 6 to 8 weeks old C57/Bl6J mice by flushing the bone marrow out with complete BMDC media (RPMI supplemented with 10% FBS, 100 U/mL penicillin/100 μg/mL streptomycin, 2 mM l-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 1× nonessential amino acids, 55 μM β-mercaptoethanol, 50 μg/mL gentamicin, and 2.5 μg/mL amphotericin B) and passing the cell suspension through a 70 μM cell strainer. Cells were cultured on nontreated 100 × 15 mm Petri dishes in complete BMDC media containing 20 ng/mL granulocyte-macrophage colony-stimulating factor (GM-CSF). Fresh media with 20 ng/mL GM-CSF was added on days 3, 5, and 7. On day 8 differentiation into dendritic cells was confirmed by measuring CD11c expression via flow cytometry using αCD11c (N418, FITC, BioLegend). Cells were then plated on nontreated 12-wells plates in complete BMDC media containing 10 ng/mL GM-CSF at 500,000 cells/well and allowed to adhere overnight. The next day cells were treated with indicated formulations and concentrations for 24 h. Following incubation, the media was removed and stored at −80 °C for cytokine analysis, then cells were scraped into PBS, washed with FACS buffer (PBS supplemented with 1% BSA), incubated with Fc-block (αCD16/32, 2.4G2, Tonbo) for 15 min at 4 °C, then stained with the appropriate antibodies for 1 h at 4 °C. The antibodies used were αCD86 (GL-1, PE/Cy7, BioLegend) and αCD11c (N418, KIRAVIA Blue 520, BioLegend). Cells were then washed with FACS buffer again and then resuspended in DAPI (1 μg/mL in FACS buffer). Flow cytometry was then run on an Amnis CellStream, and median fluorescence intensity (MFI) of CD86 was quantified.
Cytokines secreted into the media was quantified using a LEGENDplex multianalyte flow assay kit (BioLegend) following the manufacturer’s instructions using a v-bottom plate. Data was collected on a Amnis CellStream Flow Cytometer and analyzed using LEGENDplex data analysis software.

In Vitro Evaluation of Antigen Cross-Presentation

BMDCs were harvested and differentiated as described above. Cells were plated on nontreated 12-wells plates in complete BMDC media containing 10 ng/mL GM-CSF at 500,000 cells/well and allowed to adhere overnight. The next day, cells were treated with indicated formulations for 24 h. All treatment groups were 2 μM OVAp, corresponding to 3.75 ng/mL cGAMP in NP-Pep/cGAMP/MPLA(1:4), 15 ng/mL cGAMP in NP-Pep/cGAMP/MPLA(1:1), 60 ng/mL cGAMP in NP-Pep/cGAMP/MPLA(4:1) and NP-Pep/cGAMP, and 45 ng/mL MPLA in all formulations containing MPLA. The next day, cells were scraped, washed with FACS buffer (PBS supplemented with 1% BSA), incubated with Fc-block (αCD16/32, 2.4G2, Tonbo) for 15 min at 4 °C, then stained with αCD11c (N418, APC/Cy7, BioLegend) and αH-2Kb–SIINFEKL (25-D1.16, PE/Dazzle, BioLegend) for 1 h at 4 °C. Cells were then washed with FACS buffer again, resuspended in DAPI (1 μg/mL in FACS buffer), and analyzed on an Amnis CellStream Flow Cytometer.

In Vitro Evaluation of Peptide Uptake by BMDCs

BMDCs were harvested and differentiated as described above. Cells were plated on nontreated 12-well plates in complete BMDC media containing 10 ng/mL GM-CSF at 500,000 cells/well and allowed to adhere overnight. The next day, cells were treated with indicated formulations for 24 h. All treatment groups were 2 μM Cy5-labeled OVAp, corresponding to 3.75 ng/mL cGAMP in NP-Pep/cGAMP/MPLA(1:4) and NP-Pep/cGAMP, and 45 ng/mL MPLA in NP-Pep/cGAMP/MPLA(1:4). The following day, cells were scraped, washed with FACS buffer (PBS supplemented with 2% FBS), incubated with Fc-block (αCD16/32, 2.4G2, Tonbo) for 15 min at 4 °C, then stained with αCD11c (N418, FITC, BioLegend) for 1 h at 4 °C. Cells were then washed with FACS buffer, resuspended in DAPI (1 μg/mL in FACS buffer), and analyzed on an Amnis CellStream Flow Cytometer.

Animal Care

Female C57Bl/6J and B6.129S(C)-Batf3tm1Kmm/J (Batf3 knockout) mice (6–8 weeks old) were purchased from Jackson Laboratory and housed at Vanderbilt University animal facilities. All animal experiments were reviewed and approved by the Vanderbilt University Institutional Animal Care and Use Committee (IACUC).

Analysis of Nanoparticle Accumulation and Uptake in Lymph Node

C57/Bl6J mice were injected subcutaneously at the base of the tail with PBS, a soluble mix of Cy5-labeled OVAp, cGAMP, and MPLA, or NP-Pep/cGAMP/MPLA(1:4) loaded with Cy5-labled OVAp. Mice were dosed with 50 μg of OVAp, 0.08 μg of cGAMP, and 0.8 μg of MPLA. 6h after injection, the draining inguinal lymph node, spleen, and axillary lymph node (nondraining) were harvested and Cy5 fluorescence was imaged and measured with the IVIS Lumina III.
Inguinal lymph nodes were mechanically disrupted into single cell suspensions in complete RPMI (cRPMI, RPMI supplemented with 10% FBS, 100 U/mL penicillin/100 μg/mL streptomycin, 2 mM l-glutamine, and 10 mM HEPES) by forcing them through a 70 μm cell strainer. The cells were then stained with Fc-block (αCD16/32, 2.4G2, Tonbo) for 15 min at 4 °C, and then stained with the appropriate antibodies for 30 min at 4 °C. The antibodies used were eFluor 780 viability dye (eBioscience), αTCRβ (H57–597, eFluor 450, eBioscience), αCD4 (RM4–5, SB780, eBioscience), αCD8α (53–6.7, BV605, BioLegend), αCD11b (M1/70, BV510, BioLegend), αCD11c (N418, BV711, BioLegend), αGR-1 (RB6–8C5, PE/Cy7, eBioscience), αF4/80 (BM8, AF488, BioLegend), αCD19 (6D5, PE, BioLegend), and αBST2 (927, PE, BioLegend). Cells were then washed with FACS buffer (PBS supplemented with 2% FBS), fixed with 2% paraformaldehyde for 10 min, washed again with FACS buffer, and then analyzed on a Cytek Aurora flow cytometer (Figure S12, S13).

Analysis of OVA-Specific CD8+ T Cell Response in Spleen

C57/Bl6J mice were injected subcutaneously at the base of the tail on days 0, 7, and 14 with indicated formulations. Mice were dosed with 50 μg of OVAp in all formulations, and 0.8 μg of MPLA in formulations containing MPLA. NP-Pep/cGAMP/MPLA(1:4) mice were dosed with 0.08 μg of cGAMP, NP-Pep/cGAMP/MPLA(1:1) mice were dosed with 0.3125 μg of cGAMP, and NP-Pep/cGAMP/MPLA(4:1) and NP-Pep/cGAMP mice were dosed with 1.25 μg of cGAMP. On day 21, the mice were euthanized to evaluate the CD8+ T cell response in the spleen. Spleens were harvested and mechanically disrupted into single cell suspensions in cRPMI by forcing them through a 70 μm cell strainer. Red blood cells were then lysed with ACK lysis buffer, and splenocytes were resuspended in cRPMI and counted.
Splenocytes were plated at 2 × 106 cell/well in a 96-well round-bottom plate, washed twice with FACS buffer (PBS supplemented with 2% FBS and 50 μM dasatinib), stained with Fc-block (αCD16/32, 2.4G2, Tonbo) for 15 min at 4 °C, and then stained with the appropriate antibodies for 1 h at 4 °C. The antibodies used were eFluor 780 viability dye (eBioscience), αCD3e (145–2C11, BV510, BioLegend), and αCD8α (53–6.7, FITC, eBiosceince). The cells were then washed 3 times with FACS buffer and stained for 2 h at 4 °C with 1.5 μg/mL PE-labeled pOVA/H-2Kb tetramer. The cells were then washed again with FACS buffer, fixed with 2% paraformaldehyde for 10 min, wash again with FACS buffer, then analyzed on a Cytek Aurora flow cytometer (Figure S14).

Vaccination and Splenocyte Isolation for Downstream T Cell Analysis Studies

C57/Bl6J mice were injected subcutaneously at the base of the tail on days 0, 7, and 14 with indicated formulations. For studies with OVAp, NP-Pep/cGAMP/MPLA(1:4) contained 50 μg of OVAp, 0.08 μg of cGAMP, and 0.8 μg of MPLA. For studies with MC38 neoantigens, NP-Pep/cGAMP/MPLA(1:4) contained 25 μg of Reps1, 25 μg of Adpgk, 0.08 μg of cGAMP, and 0.8 μg of MPLA. On days 1, 4, 8, 11, 15, and 18, mice were administered 100 μg of αPD-1 (RMP1–14, BioXCell) intraperitoneally for indicated studies. On day 21, the mice were euthanized to evaluate the CD8+ T cell response in the spleen. Spleens were harvested and mechanically disrupted into single cell suspensions in cRPMI by forcing them through a 70 μm cell strainer. Red blood cells were then lysed with ACK lysis buffer, and splenocytes were resuspended in cRPMI and counted.

Establishment of Batf3–/– Model and Evaluation of CD8+ T Cell Response

Batf3–/– mice (The Jackson Laboratory) are knockout mice on a C57/Bl6J background that lack exons 1–2 of the Batf3 gene and are thus deficient in cross-presenting CD8α+ conventional dendritic cells (cDC1s). (74) To validate the model, splenocytes from Batf3–/– and WT mice were harvested as previously described, washed twice with FACS buffer (PBS supplemented with 2% FBS), stained with Fc-block (αCD16/32, 2.4G2, Tonbo) for 15 min at 4 °C, and then stained with the appropriate antibodies for 30 min at 4 °C. The antibodies used were eFluor 780 viability dye (eBioscience), αTCRβ (H57–597, eFluor 450, eBioscience), αCD4 (RM4–5, SB780, eBioscience), αCD8α (53–6.7, BV605, BioLegend), αCD11b (M1/70, BV510, BioLegend), αCD11c (N418, BV711, BioLegend), and αBST2 (927, PE, BioLegend). Cells were then washed with FACS buffer (PBS supplemented with 2% FBS), fixed with 2% paraformaldehyde for 10 min, washed again with FACS buffer, then analyzed on a Cytek Aurora flow cytometer to confirm that Batf3–/– mice maintained the same amount of overall CD8+ T cells but lacked cross-presenting cDC1s (Figure S15).
To evaluate the antigen-specific CD8+ T cell response, Batf3–/– and WT mice were vaccinated with the OVAp formulation and splenocytes were harvested on day 21 as described above. Splenocytes were incubated with AF647-labeled pOVA/H-2Kb tetramer for 1 h at 4 °C followed by two washes with FACS buffer (PBS supplemented with 2% FBS and 50 μM dasatinib). Nonspecific binding was inhibited via incubation in Fc-block (αCD16/32, 2.4G2, Tonbo) for 15 min at 4 °C, followed by staining with the appropriate antibodies for 30 min at 4 °C. The antibodies used were eFluor 780 viability dye (eBioscience), αTCRβ (H57–597, eFluor 450, eBioscience), αCD4 (RM4–5, SB780, eBioscience), and αCD8α (53–6.7, BV605, BioLegend). Cells were then washed twice with FACS buffer, fixed with 2% paraformaldehyde for 10 min, washed again with FACS buffer, then analyzed on a Cytek Aurora flow cytometer (Figure S16).

Analysis of Memory Phenotype

Mice were vaccinated with either OVAp or MC38 antigens as described above. Splenocytes were incubated with either AF647-labeled pOVA/H-2Kb tetramer (NIH Tetramer Core), AF647-labeled Adpgk/H-2Db tetramer (NIH Tetramer Core), or APC-labeled Reps1/H-2Db tetramer (MBL international corporation) for 1 h at 4 °C followed by two washes in FACS buffer (PBS supplemented with 2% FBS and 50 μM dasatinib). Nonspecific binding was inhibited via incubation in Fc-block (αCD16/32, 2.4G2, Tonbo) for 15 min at 4 °C, followed by staining with the appropriate antibodies for 30 min at 4 °C. The antibodies used were eFluor 780 viability dye (eBioscience), αTCR-β (S33–966, eFluor 450, eBioscience), αCD4 (RM4–5, SB780, eBioscience), αCD8α (53–6.7, AF488, Biolegend), αCD44 (IM7, PerCP, BioLegend), and αCD62L (MEL-14, BV711, BioLegend). Cells were then washed twice with FACS buffer, fixed with 2% paraformaldehyde for 10 min, washed again with FACS buffer, then analyzed on a Cytek Aurora flow cytometer (Figure S17).

Intracellular Cytokine Staining of Splenocytes

Mice were vaccinated with either OVAp or MC38 antigens and splenocytes were harvested on day 21 as described above. Splenocytes were plated at 2 × 106 cell/well in a 96-well round-bottom plate in the presence or absence of 10 mg/mL indicated peptides and incubated for 90 min at 37 °C in a CO2 incubator. Cells were then incubated with BD GolgiPlug containing Brefeldin for 5 h at 37 °C in a CO2 incubator, then washed, then stained with the appropriate surface antibodies for 45 min at 4 °C. The antibodies used were eFluor 780 viability dye (eBioscience), αCD3e-(145.2C11, PE-Cy7, Biolegend), αCD8α (53–6.7, APC-Cy7, Tonbo), and αCD4 (RM4–5, AF488, Biolegend). The cells were then fixed and permeabilized using the BD Cytofix/Cytoperm fixation/permeabilization kit (BD Biosciences) according to manufacturer’s instructions, and then cells were incubated with αIFNγ (XMG1.2, APC, BD Biosciences) and αTNFα (MP6-XT22, PE, BD Biosciences) antibodies or corresponding isotype controls. Finally, cells were washed and resuspended in FACS buffer, then analyzed on a Cytek Aurora flow cytometer (Figure S18).

Enzyme-Linked Immunosorbent Spot Assay (ELISpot)

The ELISpot assays were performed using ImmunoSpot mouse IFNg single-color kit from Cellular Technology Limited using the manufacturer’s protocol. Briefly, splenocytes were harvested as above, and 3 × 105 (for Adgpk stimulation) or 1.5 × 105 (for Reps1 stimulation) splenocytes were cultured in IFNγ precoated plates in the presence or absence of corresponding peptides for 48 h at 37 °C in a CO2 incubator. Following steps as specified by the manufacturer, plates were washed and incubated in a detection solution containing detection antibodies. After washing the detection solution, the plates were incubated in tertiary solution supplied by the manufacturer, followed by washing and incubation in blue developer solution. Plates were air-dried overnight and scanned using CTL S6 Universal-V Analyzer and ImmunoSpot software. Spots were counted by BioSpot v7.0.26.0 and the counts adjusted to obtain counts/106 cells.

Tumor Studies with EG7.OVA

For the EG7.OVA therapeutic tumor model, C57Bl/6J mice were inoculated via subcutaneous flank injection with 3 × 105 EG7.OVA cells. Mice were subcutaneously vaccinated at the base of the tail on days 7, 14, and 21 with the following groups: PBS, NP-Pep/cGAMP, NP-Pep/MPLA, NP-Pep/cGAMP/MPLA(1:4), NP-Pep/cGAMP/MPLA(1:1), or NP-Pep/cGAMP/MPLA(4:1). Mice were dosed with 50 μg of OVAp in all formulations, and 0.8 μg of MPLA in formulations containing MPLA. NP-Pep/cGAMP/MPLA(1:4) mice were dosed with 0.08 μg of cGAMP, NP-Pep/cGAMP/MPLA(1:1) mice were dosed with 0.3125 μg cGAMP, and NP-Pep/cGAMP/MPLA(4:1) and NP-Pep/cGAMP mice were dosed with 1.25 μg of cGAMP. Tumor size was measured 3 times a week with calipers using the formula V = (LxWxW)/2. Mice were euthanized at the tumor burden end point of 2000 mm3.

Tumor Studies with MC38

For the MC38 therapeutic model, C57/Bl6J mice were inoculated via subcutaneous flank injection with 1 × 106 MC38 cells. Mice were then vaccinated subcutaneously at the base of tail of days 6, 13, and 20 with the following groups: PBS, soluble mix (Reps1, Adpgk, cGAMP, and MPLA), NP-Pep/cGAMP, NP-Pep/MPLA, and NP-Pep/cGAMP/MPLA(1:4). All groups were dosed with 25 μg of Reps1 and 25 μg of Adpgk, 0.08 μg of cGAMP, and 0.8 μg of MPLA. Tumor volume was monitored as described above and mice were euthanized at the tumor burden end point of 2000 mm3.
For the MC38 therapeutic model with ICB, mice were inoculated as described above. On days 6, 13, and 20 mice were vaccinated with either PBS or NP-Pep/cGAMP/MPLA(1:4) with 25 μg of Reps1, 25 μg of Adpgk, 0.08 μg of cGAMP, and 0.8 μg of MPLA. On days 7, 10, 14, 17, 21, and 24, mice were administered 100 μg of αPD-1 (RMP1–14, BioXCell) intraperitoneally. Tumor growth was monitored as described above, and mice were euthanized at the tumor burden end point of 2000 mm3.

Statistical Analysis

Significance for each experiment was calculated as described in the figure caption using GraphPad Prism version 9.3.1. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.001. Error bars represent standard deviation unless otherwise noted. Synergy was calculated using the Loewe method on the SynergyFinder web application. (71)

Supporting Information

Click to copy section linkSection link copied!

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.3c04471.

  • Supplementary data describing polymer characterization, nanovaccine drug loading and sizing properties, BMDC costimulatory molecule expression and pro-inflammatory cytokine secretion, Loewe synergy scores, cellular uptake, tumor growth curves, and flow cytometry gating strategies (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

Click to copy section linkSection link copied!
  • Corresponding Author
    • John T. Wilson - Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States;  Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States;  Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States;  Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States;  Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States;  Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States;  Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States;  Orcidhttps://orcid.org/0000-0002-9144-2634;  Email: [email protected]
  • Authors
    • Jessalyn J. Baljon - Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    • Alexander J. Kwiatkowski - Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    • Hayden M. Pagendarm - Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States;  Orcidhttps://orcid.org/0000-0001-7611-6120
    • Payton T. Stone - Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    • Amrendra Kumar - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    • Vijaya Bharti - Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    • Jacob A. Schulman - Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States
    • Kyle W. Becker - Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee 37235, United States;  Orcidhttps://orcid.org/0000-0003-1627-2724
    • Eric W. Roth - Northwestern University Atomic and Nanoscale Characterization Experimental (NUANCE) Center, Northwestern University, Evanston, Illinois 60208, United States
    • Plamen P. Christov - Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
    • Sebastian Joyce - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States;  Department of Veteran Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States;  Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States;  Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
  • Author Contributions

    J.J.B. and J.T.W. designed the experiments. J.J.B., A.J.K., H.M.P., K.W.B., P.T.S., A.J.K., V.B., J.A.S., P.P.C., and E.W.R. performed the experiments. P.P.C., E.W.R., S.J., and J.T.W. provided resources. J.J.B. and J.T.W. wrote the manuscript. J.T.W. supervised the study. S.J. and J.T.W. provided funding.

  • Notes
    The authors declare the following competing financial interest(s): J.T.W. is an inventor on U.S. Patent 10,696,985 Reversibly Crosslinked Endosomolytic Polymer Vesicles for Cytosolic Drug Delivery and on U.S. Patent Application PCT/US2019/058945 Graft Copolymers, Methods of Forming Graft Copolymers, and Methods of Use Thereof, both of which describe drug delivery technologies that have been used for STING agonist delivery.

Acknowledgments

Click to copy section linkSection link copied!

We gratefully acknowledge C. Duvall for use of IVIS imaging equipment. Additionally, we thank the core facilities of the Vanderbilt Institute of Nanoscale Sciences and Engineering (VINSE) for use of dynamic light scattering, the VUMC Flow Cytometry Shared Resource supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404), and the Vanderbilt Mass Spectrometry Research Center (MSRC) for use of mass spectrometry. We also acknowledge M.J. Munson for providing the Gal9-mCherry H358 cells. Additionally, the cryoTEM work made use of the BioCryo facility of Northwestern University’s NUANCE center, which has received support from the SHyNE Resource (NSF ECCS-2025633), and IIN, and Northwestern’s MRSEC program (NSF DMR-1720139). 2′3′-cGAMP was provided by the Vanderbilt Institute of Chemical Biology Chemical Synthesis Core. Experiments were performed in the Vanderbilt High-Throughput Screening (HTS) Core Facility with assistance provided by Joshua A. Bauer and David Baughman. The HTS Core receives support from the Vanderbilt Institute of Chemical Biology and the Vanderbilt Ingram Cancer Center (P30 CA68485). This work was supported by grants from the National Science Foundation CBET-1554623 (J.T.W), the National Institutes of Health (NIH) R01CA266767 (J.T.W), R01DE027749 (S.J.), F31CA257275-01 (J.J.B.), the NIH Integrated in Engineering and Diabetes Training Grant (T32DK101003, H.M.P), the NIH Microenvironmental Influences in Cancer Training Grant (T32CA009592, A.J.K),the NIH Chemical-Biology Interface Training Grant (T32GM065086, P.T.S), a Vanderbilt Ingram Cancer Center Scholarship (J.T.W.), a Veteran’s Affairs RCS Award IK6 BX004595 (S.J.) and Merit Awards I01 BX001444 and BX001610 (S.J.), and a Stand Up To Cancer Innovative Research Grant, grant number SU2C-AACR-IRG- 20-17 (J.T.W.)Stand Up to Cancer (SU2C) is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. H.M.P and P.T.S. acknowledge funding support through the National Science Foundation Graduate Research Fellowship Program under grant number 1937963. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

References

Click to copy section linkSection link copied!

This article references 78 other publications.

  1. 1
    Korman, A. J.; Garrett-Thomson, S. C.; Lonberg, N. The Foundations of Immune Checkpoint Blockade and the Ipilimumab Approval Decennial. Nat. Rev. Drug Discov 2022, 21, 509– 528,  DOI: 10.1038/s41573-021-00345-8
    Google Scholar
    1
    The foundations of immune checkpoint blockade and the ipilimumab approval decennial
    Korman, Alan J.; Garrett-Thomson, Sarah C.; Lonberg, Nils
    Nature Reviews Drug Discovery (2022), 21 (7), 509-528CODEN: NRDDAG; ISSN:1474-1776. (Nature Portfolio)
    Cancer immunity, and the potential for cancer immunotherapy, have been topics of scientific discussion and experimentation for over a hundred years. Several successful cancer immunotherapies - such as IL-2 and interferon-a (IFNa) - have appeared over the past 30 years. However, it is only in the past decade that immunotherapy has made a broad impact on patient survival in multiple high-incidence cancer indications. The emergence of immunotherapy as a new pillar of cancer treatment (adding to surgery, radiation, chemotherapy and targeted therapies) is due to the success of immune checkpoint blockade (ICB) drugs, the first of which - ipilimumab - was approved in 2011. ICB drugs block receptors and ligands involved in pathways that attenuate T cell activation - such as cytotoxic T lymphocyte antigen 4 (CTLA4), programed cell death 1 (PD1) and its ligand, PDL1 - and prevent, or reverse, acquired peripheral tolerance to tumor antigens. In this Review we mark the tenth anniversary of the approval of ipilimumab and discuss the foundational scientific history of ICB, together with the history of the discovery, development and elucidation of the mechanism of action of the first generation of drugs targeting the CTLA4 and PD1 pathways.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXivValtr%252FJ&md5=4d70b7f025350759038f63b701a6c494
  2. 2
    Sharma, P.; Allison, J. P. The Future of Immune Checkpoint Therapy. Science 2015, 348, 56– 61,  DOI: 10.1126/science.aaa8172
    Google Scholar
    2
    The future of immune checkpoint therapy
    Sharma, Padmanee; Allison, James P.
    Science (Washington, DC, United States) (2015), 348 (6230), 56-61CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    A review. Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clin. advances and provided a new weapon against cancer. This therapy has elicited durable clin. responses and, in a fraction of patients, long-term remissions where patients exhibit no clin. signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of addnl. pathways that will need to be targeted through combination therapies to provide survival benefit for greater nos. of patients.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXls1Wmurg%253D&md5=d63ae85b9c651ec64a3b5b002c609e35
  3. 3
    Shum, B.; Larkin, J.; Turajlic, S. Predictive Biomarkers for Response to Immune Checkpoint Inhibition. Semin Cancer Biol. 2022, 79, 4– 17,  DOI: 10.1016/j.semcancer.2021.03.036
    Google Scholar
    3
    Predictive biomarkers for response to immune checkpoint inhibition
    Shum, Benjamin; Larkin, James; Turajlic, Samra
    Seminars in Cancer Biology (2022), 79 (), 4-17CODEN: SECBE7; ISSN:1044-579X. (Elsevier Ltd.)
    A review. Immune checkpoint inhibitors have transformed the prognosis and treatment paradigm of many cancer types, through the potential for durable responses. However, the majority of patients still do not benefit. Response to checkpoint inhibition is detd. by dynamic host, tumor and tumor microenvironment factors that display spatial and temporal variability, but our understanding of these interactions is incomplete. Through investigating biomarkers of resistance and response, opportunities arise to discover new therapeutic targets and shape personalised treatment strategies. Here we review approved and emerging biomarkers of response to immune checkpoint inhibitors, in particular the recent rapid progress in host and tumor genomics. It is unlikely that a single biomarker will precisely predict response, but multivariate multiomic markers may provide a balanced assessment of these factors and more accurately identify patients who will benefit. Further efforts are required to translate these groundbreaking discoveries into novel therapeutics and biomarker driven clin. trials, to provide durable treatment response to a greater population of patients.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtlWqt7jK&md5=17802852fefce3fedc8ce6b596fd7510
  4. 4
    Jenkins, R. W.; Barbie, D. A.; Flaherty, K. T. Mechanisms of Resistance to Immune Checkpoint Inhibitors. Br. J. Cancer 2018, 118, 9– 16,  DOI: 10.1038/bjc.2017.434
    Google Scholar
    4
    Mechanisms of resistance to immune checkpoint inhibitors
    Jenkins, Russell W.; Barbie, David A.; Flaherty, Keith T.
    British Journal of Cancer (2018), 118 (1), 9-16CODEN: BJCAAI; ISSN:0007-0920. (Nature Research)
    Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clin. activity in several types of cancer and are rapidly transforming the practice of medical oncol. Whereas cytotoxic chemotherapy and small mol. inhibitors ('targeted therapies') largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumor immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunol. memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addn., late relapses are now emerging with longer follow-up of clin. trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clin. response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clin. studies and correlative clin. data. Improved understanding of mol. and immunol. mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clin. and pre-clin. data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlGmsQ%253D%253D&md5=98d6734fe4172247aa9402fd388159df
  5. 5
    Ye, Z.; Qian, Q.; Jin, H.; Qian, Q. Cancer Vaccine: Learning Lessons from Immune Checkpoint Inhibitors. J. Cancer 2018, 9, 263– 268,  DOI: 10.7150/jca.20059
    Google Scholar
    5
    Cancer vaccine: learning lessons from immune checkpoint inhibitors
    Ye ZhenLong; Qian Qiming; Jin HuaJun; Qian QiJun
    Journal of Cancer (2018), 9 (2), 263-268 ISSN:1837-9664.
    Cancer vaccines have been exclusively studied all through the past decades, and have made exceptional achievements in cancer treatment. Few cancer vaccines have been approved by the US Food and Drug Administration (FDA), for instance, Provenge, which was approved for the treatment of prostate carcinoma in 2012. Moreover, more recently, T-VEC got approval for the treatment of melanoma. While, the overall therapeutic effects of cancer vaccines have been taken into consideration as below expectations, low antigenicity of targeting antigen and tumor heterogeneity are the two key limiting barriers encountered by the cancer vaccines. Nonetheless, recent developments in cancer immune-therapies together with associated technologies, for instance the unparalleled achievements bagged by immune checkpoint inhibitor based therapies and neo-antigen identification tools, envisage potential improvements in cancer vaccines in respect to the treatments of malignancies. This review brings forth measures for the purpose of refining therapeutic cancer vaccines by learning lessons from the success of PD-1 inhibitor based immune-therapies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvhslGhtQ%253D%253D&md5=c878c5e7ffce77d94296fce9ae06908a
  6. 6
    Lin, M. J.; Svensson-Arvelund, J.; Lubitz, G. S.; Marabelle, A.; Melero, I.; Brown, B. D.; Brody, J. D. Cancer Vaccines: The Next Immunotherapy Frontier. Nat. Cancer 2022, 3, 911– 926,  DOI: 10.1038/s43018-022-00418-6
    Google Scholar
    6
    Cancer vaccines: the next immunotherapy frontier
    Lin, Matthew J.; Svensson-Arvelund, Judit; Lubitz, Gabrielle S.; Marabelle, Aurelien; Melero, Ignacio; Brown, Brian D.; Brody, Joshua D.
    Nature Cancer (2022), 3 (8), 911-926CODEN: NCAADQ; ISSN:2662-1347. (Springer International Publishing AG)
    A review. After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other std.-of-care immunotherapies, but they have yet to realize their full potential and expand the oncol. armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clin. development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitlCit7jE&md5=47262a65ec90f090054e453a5bae8b98
  7. 7
    Curran, M. A.; Glisson, B. S. New Hope for Therapeutic Cancer Vaccines in the Era of Immune Checkpoint Modulation. Annu. Rev. Med. 2019, 70, 409– 424,  DOI: 10.1146/annurev-med-050217-121900
    Google Scholar
    7
    New Hope for Therapeutic Cancer Vaccines in the Era of Immune Checkpoint Modulation
    Curran, Michael A.; Glisson, Bonnie S.
    Annual Review of Medicine (2019), 70 (), 409-424CODEN: ARMCAH; ISSN:0066-4219. (Annual Reviews)
    A review. The driver and passenger mutations accumulated in the process of malignant transformation offer an adequate spectrum of immune visible alterations to the cellular proteome and resulting peptidome to render these cancers targetable-and, in theory, rejectable-by the host T cell immune response. In addn., cancers often overexpress tissue-specific and developmental antigens to which immune tolerance is incomplete. Sometimes, virally transferred oncogenes drive malignant transformation and remain expressed throughout the cancer. Despite this state of antigenic sufficiency, cancer grows progressively and overcomes all efforts of the host immune system to contain it. While therapeutic cancer vaccination can mobilize high frequencies of tumor-specific T cells, these responses remain subject to intratumoral attenuation. Antibody modulation of T cell function through checkpoint blockade or costimulatory activation can restore survival, proliferation, and effector function to these tumor-infiltrating T cells and convert otherwise subtherapeutic vaccines into potentially curative cancer immunotherapeutics.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVGksLzI&md5=58f81e23d229c445006c8672cf6b338b
  8. 8
    Shae, D.; Baljon, J. J.; Wehbe, M.; Becker, K. W.; Sheehy, T. L.; Wilson, J. T. At the Bench: Engineering the Next Generation of Cancer Vaccines. J. Leukoc Biol. 2020, 108, 1435– 1453,  DOI: 10.1002/JLB.5BT0119-016R
    Google Scholar
    8
    At the bench: Engineering the next generation of cancer vaccines
    Shae, Daniel; Baljon, Jessalyn J.; Wehbe, Mohamed; Becker, Kyle W.; Sheehy, Taylor L.; Wilson, John Tanner
    Journal of Leukocyte Biology (2020), 108 (4), 1435-1453CODEN: JLBIE7; ISSN:1938-3673. (John Wiley & Sons, Inc.)
    A review. Cancer vaccines hold promise as an immunotherapeutic modality based on their potential to generate tumor antigen-specific T cell responses and long-lived antitumor responses capable of combating metastatic disease and recurrence. However, cancer vaccines have historically failed to deliver significant therapeutic benefit in the clinic, which we maintain is due in part to drug delivery challenges that have limited vaccine immunogenicity and efficacy. In this review, we examine some of the known and putative failure mechanisms of common first-generation clin. cancer vaccines, and describe how the rational design of materials engineered for vaccine delivery and immunomodulation can address these shortcomings. First, we outline vaccine design principles for augmenting cellular immunity to tumor antigens and describe how well-engineered materials can improve vaccine efficacy, highlighting recent innovations in vaccine delivery technol. that are primed for integration into neoantigen vaccine development pipelines. We also discuss the importance of sequencing, timing, and kinetics in mounting effective immune responses to cancer vaccines, and highlight examples of materials that potentiate antitumor immunity through spatiotemporal control of immunomodulation. Furthermore, we describe several engineering strategies for improving outcomes of in situ cancer vaccines, which leverage local, intratumoral delivery to stimulate systemic immunity. Finally, we highlight recent innovations leveraging nanotechnol. for increasing the immunogenicity of the tumor microenvironment (TME), which is crit. to enhancing tumor infiltration and function of T cells elicited in response to cancer vaccines. These immunoengineering strategies and tools complement ongoing advances in cancer vaccines as they reemerge as an important component of the immunotherapeutic armamentarium.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ShsrbN&md5=cd67858ef425a0f35c2b527fcf950ea3
  9. 9
    Kleponis, J.; Skelton, R.; Zheng, L. Fueling the Engine and Releasing the Break: Combinational Therapy of Cancer Vaccines and Immune Checkpoint Inhibitors. Cancer Biol. Med. 2015, 12, 201– 208,  DOI: 10.7497/j.issn.2095-3941.2015.0046
    Google Scholar
    9
    Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors
    Kleponis, Jennifer; Skelton, Richard; Zheng, Lei
    Cancer Biology & Medicine (2015), 12 (3Spec.Iss.), 201-208CODEN: CBMADQ ISSN:. (Tianjin Medical University Cancer Institute and Hospital)
    Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clin. trials to test the combination are currently ongoing.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlslGjsbY%253D&md5=98c84619ccf7224c4d30882d091a89a5
  10. 10
    Shemesh, C. S.; Hsu, J. C.; Hosseini, I.; Shen, B. Q.; Rotte, A.; Twomey, P.; Girish, S.; Wu, B. Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities. Mol. Ther 2021, 29, 555– 570,  DOI: 10.1016/j.ymthe.2020.09.038
    Google Scholar
    10
    Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities
    Shemesh, Colby S.; Hsu, Joy C.; Hosseini, Iraj; Shen, Ben-Quan; Rotte, Anand; Twomey, Patrick; Girish, Sandhya; Wu, Benjamin
    Molecular Therapy (2021), 29 (2), 555-570CODEN: MTOHCK; ISSN:1525-0024. (Cell Press)
    A review. Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8+ and CD4+ T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clin. practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. I.v. or i.m. administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quant. methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjsVCmsLY%253D&md5=020291133534cc7a2697ae7101562a6c
  11. 11
    Zhao, J.; Chen, Y.; Ding, Z. Y.; Liu, J. Y. Safety and Efficacy of Therapeutic Cancer Vaccines Alone or in Combination with Immune Checkpoint Inhibitors in Cancer Treatment. Front Pharmacol 2019, 10, 1184,  DOI: 10.3389/fphar.2019.01184
    Google Scholar
    11
    Safety and efficacy of therapeutic cancer vaccines alone or in combination with immune checkpoint inhibitors in cancer treatment
    Zhao, Jing; Chen, Ye; Ding, Zhen-Yu.; Liu, Ji-Yan
    Frontiers in Pharmacology (2019), 10 (), 1184CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
    A review. Therapeutic cancer vaccines have proven to seldom induce dramatic clin. response when used alone, and therefore, they are being studied in combination with addnl. treatment modalities to achieve optimal treatment activities. Growing preclin. data show that combining vaccines and immune checkpoint inhibitors (ICIs) can prime intensified immunogenicity and modulate immunosuppressive tumor microenvironment. Herein, we focus on the safety and efficacy of approved and promising cancer vaccines alone or combined with ICIs in the treatment of several malignancies. Generally, the majority of clin. trials support the concept of synergy that combination therapy of vaccines and ICIs holds maximized potential to improve clin. outcomes. Importantly, the combination has acceptable safety and minimal addnl. toxicity compared with single-agent vaccines or ICIs. Addnl., the potential strategies of combining personalized tumor vaccines with ICIs will become priority option and future direction of vaccine development and application and the urgent need to develop effective biomarkers to screen appropriate patient populations and predict response to combination therapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvVeqtLk%253D&md5=b9137c6f5bd286e8db5eb610319bab4b
  12. 12
    Blass, E.; Ott, P. A. Advances in the Development of Personalized Neoantigen-Based Therapeutic Cancer Vaccines. Nat. Rev. Clin Oncol 2021, 18, 215– 229,  DOI: 10.1038/s41571-020-00460-2
    Google Scholar
    12
    Advances in the development of personalized neoantigen-based therapeutic cancer vaccines
    Blass Eryn; Ott Patrick A; Ott Patrick A; Ott Patrick A; Ott Patrick A
    Nature reviews. Clinical oncology (2021), 18 (4), 215-229 ISSN:.
    Within the past decade, the field of immunotherapy has revolutionized the treatment of many cancers with the development and regulatory approval of various immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies in diverse indications. Another promising approach to cancer immunotherapy involves the use of personalized vaccines designed to trigger de novo T cell responses against neoantigens, which are highly specific to tumours of individual patients, in order to amplify and broaden the endogenous repertoire of tumour-specific T cells. Results from initial clinical studies of personalized neoantigen-based vaccines, enabled by the availability of rapid and cost-effective sequencing and bioinformatics technologies, have demonstrated robust tumour-specific immunogenicity and preliminary evidence of antitumour activity in patients with melanoma and other cancers. Herein, we provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, review the types of vaccine-induced T cells that are found within tumours and outline strategies to enhance the T cell responses. In addition, we discuss the current status of clinical studies testing personalized neoantigen vaccines in patients with cancer and considerations for future clinical investigation of this novel, individualized approach to immunotherapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3srivFOqtQ%253D%253D&md5=82c721ffe87a85367bc1081598d18a5d
  13. 13
    Schumacher, T. N.; Scheper, W.; Kvistborg, P. Cancer Neoantigens. Annu. Rev. Immunol. 2019, 37, 173– 200,  DOI: 10.1146/annurev-immunol-042617-053402
    Google Scholar
    13
    Cancer Neoantigens
    Schumacher, Ton N.; Scheper, Wouter; Kvistborg, Pia
    Annual Review of Immunology (2019), 37 (), 173-200CODEN: ARIMDU; ISSN:0732-0582. (Annual Reviews)
    A review. Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell-based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clin. activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biol. properties of these antigens. We discuss recent technol. advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clin. interventions.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFejsLfP&md5=21b8e70354a6e489f6f56f526f2f08ba
  14. 14
    Janes, M. E.; Gottlieb, A. P.; Park, K. S.; Zhao, Z.; Mitragotri, S. Cancer Vaccines in the Clinic. Bioeng Transl Med. 2024, 9, e10588  DOI: 10.1002/btm2.10588
    Google Scholar
    There is no corresponding record for this reference.
  15. 15
    Baljon, J. J.; Wilson, J. T. Bioinspired Vaccines to Enhance Mhc Class-I Antigen Cross-Presentation. Curr. Opin Immunol 2022, 77, 102215,  DOI: 10.1016/j.coi.2022.102215
    Google Scholar
    15
    Bioinspired vaccines to enhance MHC class-I antigen cross-presentation
    Baljon, Jessalyn J.; Wilson, John T.
    Current Opinion in Immunology (2022), 77 (), 102215CODEN: COPIEL; ISSN:0952-7915. (Elsevier Ltd.)
    A review. Here, we briefly summarize known cross-presentation pathways and highlight how synthetic vaccines can be engineered to enhance MHC-I presentation of exogenous peptide and protein antigens by professional antigen-presenting cells (APCs). In particular, we summarize how mol. engineering and nanotechnol. are being harnessed to enhance antigen delivery to lymph nodes and to cross-presenting dendritic cells, to bypass endosomal trafficking of exogenous antigen to promote delivery of antigen to the cytosol of APCs, and to coordinate the delivery of antigen with immune-stimulating adjuvants that can act synergistically to augment antigen cross-presentation. Cross-presentation of exogenous antigen on MHC class-I is a crucial process for generating a CD8+ T cell response, and is therefore an important design consideration in the development of T-cell-engaging vaccines against viruses, intracellular bacteria, and cancers.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhtl2jtr7M&md5=66ac8dde3eed78c8f43ac96caae336fe
  16. 16
    Liu, W.; Tang, H.; Li, L.; Wang, X.; Yu, Z.; Li, J. Peptide-Based Therapeutic Cancer Vaccine: Current Trends in Clinical Application. Cell Prolif 2021, 54, e13025  DOI: 10.1111/cpr.13025
    Google Scholar
    16
    Peptide-based therapeutic cancer vaccine: Current trends in clinical application
    Liu, Wensi; Tang, Haichao; Li, Luanfeng; Wang, Xiangyi; Yu, Zhaojin; Li, Jianping
    Cell Proliferation (2021), 54 (5), e13025CODEN: CPROEM; ISSN:0960-7722. (John Wiley & Sons Ltd.)
    A review. The peptide-based therapeutic cancer vaccines have attracted enormous attention in recent years as one of the effective treatments of tumor immunotherapy. Most of peptide-based vaccines are based on epitope peptides stimulating CD8+ T cells or CD4+ T helper cells to target tumor-assocd. antigens (TAAs) or tumor-specific antigens (TSAs). Some adjuvants and nanomaterials have been exploited to optimize the efficiency of immune response of the epitope peptide to improve its clin. application. At present, numerous peptide-based therapeutic cancer vaccines have been developed and achieved significant clin. benefits. Similarly, the combination of peptide-based vaccines and other therapies has demonstrated a superior efficacy in improving anti-cancer activity. We delve deeper into the choices of targets, design and screening of epitope peptides, clin. efficacy and adverse events of peptide-based vaccines, and strategies combination of peptide-based therapeutic cancer vaccines and other therapies. The review will provide a detailed overview and basis for future clin. application of peptide-based therapeutic cancer vaccines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVWrtLfK&md5=00a6a94c14b8864a77e1fcce50f5f785
  17. 17
    Stephens, A. J.; Burgess-Brown, N. A.; Jiang, S. Beyond Just Peptide Antigens: The Complex World of Peptide-Based Cancer Vaccines. Front Immunol 2021, 12, 696791,  DOI: 10.3389/fimmu.2021.696791
    Google Scholar
    17
    Beyond just peptide antigens: the complex world of peptide-based cancer vaccines
    Stephens, Alexander J.; Burgess-Brown, Nicola A.; Jiang, Shisong
    Frontiers in Immunology (2021), 12 (), 696791CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    A review. Peptide-based cancer vaccines rely upon the strong activation of the adaptive immune response to elicit its effector function. They have shown to be highly specific and safe, but have yet to prove themselves as an efficacious treatment for cancer in the clinic. This is for a variety of reasons, including tumor heterogeneity, self-tolerance, and immune suppression. Importance has been placed on the overall design of peptide-based cancer vaccines, which have evolved from simple peptide derivs. of a cancer antigen, to complex drugs; incorporating overlapping regions, conjugates, and delivery systems to target and stimulate different components of antigen presenting cells, and to bolster antigen cross-presentation. Peptide-based cancer vaccines are increasingly becoming more personalised to an individuals tumor antigen repertoire and are often combined with existing cancer treatments. This strategy ultimately aids in combating the shortcomings of a more generalised vaccine strategy and provides a comprehensive treatment, taking into consideration cancer cell variability and its ability to avoid immune interrogation.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFOitrvK&md5=d642fe90d7d555cd18312a800d8be80f
  18. 18
    Yewdell, J. W. Designing CD8+ T Cell Vaccines: It’s Not Rocket Science (Yet). Curr. Opin Immunol 2010, 22, 402– 410,  DOI: 10.1016/j.coi.2010.04.002
    Google Scholar
    18
    Designing CD8+ T cell vaccines: it's not rocket science (yet)
    Yewdell, Jonathan W.
    Current Opinion in Immunology (2010), 22 (3), 402-410CODEN: COPIEL; ISSN:0952-7915. (Elsevier B.V.)
    A review. CD8+ T cells play important roles in clearing viral infections and eradicating tumors. Designing vaccines that elicit effective CD8+ T cell responses requires a thorough knowledge of the pathways of antigen presentation in vivo. Here, I review recent progress in understanding the activation of naive CD8+ T cells in vivo, with particular emphasis on cross-priming, the presentation of protein antigens acquired by dendritic cells from their environment. With the rapid advances in this area of research, the dawn of rational vaccine design is at hand.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntV2jsbk%253D&md5=f6f6853cd382fab6b98cb14088f25b2f
  19. 19
    Khong, H.; Overwijk, W. W. Adjuvants for Peptide-Based Cancer Vaccines. J. Immunother Cancer 2016, 4, 56,  DOI: 10.1186/s40425-016-0160-y
    Google Scholar
    19
    Adjuvants for peptide-based cancer vaccines
    Khong Hiep; Overwijk Willem W
    Journal for immunotherapy of cancer (2016), 4 (), 56 ISSN:2051-1426.
    Cancer therapies based on T cells have shown impressive clinical benefit. In particular, immune checkpoint blockade therapies with anti-CTLA-4 and anti-PD-1/PD-L1 are causing dramatic tumor shrinkage and prolonged patient survival in a variety of cancers. However, many patients do not benefit, possibly due to insufficient spontaneous T cell reactivity against their tumors and/or lacking immune cell infiltration to tumor site. Such tumor-specific T cell responses could be induced through anti-cancer vaccination; but despite great success in animal models, only a few of many cancer vaccine trials have demonstrated robust clinical benefit. One reason for this difference may be the use of potent, effective vaccine adjuvants in animal models, vs. the use of safe, but very weak, vaccine adjuvants in clinical trials. As vaccine adjuvants dictate the type and magnitude of the T cell response after vaccination, it is critical to understand how they work to design safe, but also effective, cancer vaccines for clinical use. Here we discuss current insights into the mechanism of action and practical application of vaccine adjuvants, with a focus on peptide-based cancer vaccines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svjtl2ntw%253D%253D&md5=caffd368c197f407b12a8b1264be8038
  20. 20
    Gouttefangeas, C.; Rammensee, H. G. Personalized Cancer Vaccines: Adjuvants Are Important, Too. Cancer Immunol Immunother 2018, 67, 1911– 1918,  DOI: 10.1007/s00262-018-2158-4
    Google Scholar
    20
    Personalized cancer vaccines: adjuvants are important, too
    Gouttefangeas, Cecile; Rammensee, Hans-Georg
    Cancer Immunology Immunotherapy (2018), 67 (12), 1911-1918CODEN: CIIMDN; ISSN:0340-7004. (Springer)
    Therapeutic cancer vaccines have shown limited clin. efficacy so far. Nevertheless, in the meantime, our understanding of immune cell function and the interactions of immune cells with growing tumors has advanced considerably. We are now in a position to invest this knowledge into the design of more powerful vaccines and therapy combinations aimed at increasing immunogenicity and decreasing tumor-induced immunosuppression. This review focuses essentially on peptide-based human vaccines. We will discuss two aspects that are crit. for increasing their intrinsic immunogenicity: the selection of the antigen(s) to be targeted, and the as yet unmet need for strong adjuvants.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsVGqsrc%253D&md5=f0bb1792ca78fcf2e11b427377a3cd44
  21. 21
    Temizoz, B.; Kuroda, E.; Ishii, K. J. Vaccine Adjuvants as Potential Cancer Immunotherapeutics. Int. Immunol. 2016, 28, 329– 338,  DOI: 10.1093/intimm/dxw015
    Google Scholar
    21
    Vaccine adjuvants as potential cancer immunotherapeutics
    Temizoz, Burcu; Kuroda, Etsushi; Ishii, Ken J.
    International Immunology (2016), 28 (7), 329-338CODEN: INIMEN; ISSN:0953-8178. (Oxford University Press)
    Accumulated evidence obtained from various clin. trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clin. trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFOru7fE&md5=92aa03134406c55673017cb24da45eb4
  22. 22
    Kaur, A.; Baldwin, J.; Brar, D.; Salunke, D. B.; Petrovsky, N. Toll-Like Receptor (TLR) Agonists as a Driving Force Behind Next-Generation Vaccine Adjuvants and Cancer Therapeutics. Curr. Opin Chem. Biol. 2022, 70, 102172,  DOI: 10.1016/j.cbpa.2022.102172
    Google Scholar
    22
    Toll-like receptor (TLR) agonists as a driving force behind next-generation vaccine adjuvants and cancer therapeutics
    Kaur, Arshpreet; Baldwin, Jeremy; Brar, Deshkanwar; Salunke, Deepak B.; Petrovsky, Nikolai
    Current Opinion in Chemical Biology (2022), 70 (), 102172CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
    A review until recently, the development of new human adjuvants was held back by a poor understanding of their mechanisms of action. The field was revolutionized by the discovery of the toll-like receptors (TLRs), innate immune receptors that directly or indirectly are responsible for detecting pathogen-assocd. mol. patterns (PAMPs) and respond to them by activating innate and adaptive immune pathways. Hundreds of ligands targeting various TLRs have since been identified and characterized as vaccine adjuvants. This work has important implications not only for the development of vaccines against infectious diseases but also for immuno-therapies against cancer, allergy, Alzheimer's disease, drug addiction and other diseases. Each TLR has its own specific tissue localization and downstream gene pathways, providing researchers the opportunity to precisely tailor adjuvants with specific immune effects. TLR agonists can be combined with other TLR or alternative adjuvants to create combination adjuvants with synergistic or modulatory effects. This review provides an introduction to the various classes of TLR adjuvants and their resp. pathways. It provides an overview of recent advancements in the TLR field in the past 2-3 years and discusses criteria for selecting specific TLR adjuvants based on considerations, such as disease mechanisms and correlates of protection, TLR immune biasing capabilities, route of administration, antigen compatibility, new vaccine technol. platforms, and age- and species-specific effects.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhs1yitbnL&md5=3150d579bdb7406e044934c74a7af2cd
  23. 23
    Hu, H. G.; Li, Y. M. Emerging Adjuvants for Cancer Immunotherapy. Front Chem. 2020, 8, 601,  DOI: 10.3389/fchem.2020.00601
    Google Scholar
    23
    Emerging adjuvants for cancer immunotherapy
    Hu, Hong-Guo; Li, Yan-Mei
    Frontiers in Chemistry (Lausanne, Switzerland) (2020), 8 (), 601CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
    A review. Cancer is a life-threatening disease, and immunotherapies have been developed as a novel, potent treatment for cancer. Adjuvants, used alone or in combination with other agents, play crucial roles in immune activation. This is necessary for cancer immunotherapy, particularly in the construction of therapeutic cancer vaccines. Adjuvants activate antigen-presenting cells and promote the presentation of antigen epitopes on major histocompatibility complex mols., further enhancing adaptive immune responses, including cytotoxic T lymphocytes, to elicit cancer-cell death. However, the applications of adjuvants are limited by their poor efficacy or insufficient safety. In recent studies, researchers attempted to develop safe, efficacious adjuvants for cancer immunotherapy, and many compds. (including inorg. compds., org. mols., polymers, and colloids) have been identified and optimized as agonists of various pathways. In this , we focus on the discovery and structural design of emerging adjuvants and discuss how these findings benefit healthcare.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFWit7vF&md5=03aa3cb231a4e3245efde5c3e6959b61
  24. 24
    Paston, S. J.; Brentville, V. A.; Symonds, P.; Durrant, L. G. Cancer Vaccines, Adjuvants, and Delivery Systems. Front Immunol 2021, 12, 627932,  DOI: 10.3389/fimmu.2021.627932
    Google Scholar
    24
    Cancer vaccines, adjuvants, and delivery systems
    Paston, Samantha j.; Brentville, Victoria a.; Symonds, Peter; Durrant, Lindy g.
    Frontiers in Immunology (2021), 12 (), 627932CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    A review. Vaccination was first pioneered in the 18th century by Edward Jenner and eventually led to the development of the smallpox vaccine and subsequently the eradication of smallpox. The impact of vaccination to prevent infectious diseases has been outstanding with many infections being prevented and a significant decrease in mortality worldwide. Cancer vaccines aim to clear active disease instead of aiming to prevent disease, the only exception being the recently approved vaccine that prevents cancers caused by the Human Papillomavirus. The development of therapeutic cancer vaccines has been disappointing with many early cancer vaccines that showed promise in preclin. models often failing to translate into efficacy in the clinic. In this review we provide an overview of the current vaccine platforms, adjuvants and delivery systems that are currently being investigated or have been approved. With the advent of immune checkpoint inhibitors, we also review the potential of these to be used with cancer vaccines to improve efficacy and help to overcome the immune suppressive tumor microenvironment.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXpvVyhtrg%253D&md5=3d9e90696dda37b5ab117b67a282262d
  25. 25
    Keskin, D. B.; Anandappa, A. J.; Sun, J.; Tirosh, I.; Mathewson, N. D.; Li, S.; Oliveira, G.; Giobbie-Hurder, A.; Felt, K.; Gjini, E. Neoantigen Vaccine Generates Intratumoral T Cell Responses in Phase Ib Glioblastoma Trial. Nature 2019, 565, 234– 239,  DOI: 10.1038/s41586-018-0792-9
    Google Scholar
    25
    Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial
    Keskin, Derin B.; Anandappa, Annabelle J.; Sun, Jing; Tirosh, Itay; Mathewson, Nathan D.; Li, Shuqiang; Oliveira, Giacomo; Giobbie-Hurder, Anita; Felt, Kristen; Gjini, Evisa; Shukla, Sachet A.; Hu, Zhuting; Li, Letitia; Le, Phuong M.; Allesoee, Rosa L.; Richman, Alyssa R.; Kowalczyk, Monika S.; Abdelrahman, Sara; Geduldig, Jack E.; Charbonneau, Sarah; Pelton, Kristine; Iorgulescu, J. Bryan; Elagina, Liudmila; Zhang, Wandi; Olive, Oriol; McCluskey, Christine; Olsen, Lars R.; Stevens, Jonathan; Lane, William J.; Salazar, Andres M.; Daley, Heather; Wen, Patrick Y.; Chiocca, E. Antonio; Harden, Maegan; Lennon, Niall J.; Gabriel, Stacey; Getz, Gad; Lander, Eric S.; Regev, Aviv; Ritz, Jerome; Neuberg, Donna; Rodig, Scott J.; Ligon, Keith L.; Suva, Mario L.; Wucherpfennig, Kai W.; Hacohen, Nir; Fritsch, Edward F.; Livak, Kenneth J.; Ott, Patrick A.; Wu, Catherine J.; Reardon, David A.
    Nature (London, United Kingdom) (2019), 565 (7738), 234-239CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Neoantigens, which are derived from tumor-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumor rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumors such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunol. 'cold' tumor microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral edema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the no. of tumor-infiltrating T cells. Using single-cell T cell receptor anal., we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumor. Neoantigen-targeting vaccines thus have the potential to favorably alter the immune milieu of glioblastoma.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFyksLvE&md5=665425d605411ebfd4764314e7d1f220
  26. 26
    Ott, P. A.; Hu, Z.; Keskin, D. B.; Shukla, S. A.; Sun, J.; Bozym, D. J.; Zhang, W.; Luoma, A.; Giobbie-Hurder, A.; Peter, L.; Chen, C.; Olive, O.; Carter, T. A.; Li, S.; Lieb, D. J.; Eisenhaure, T.; Gjini, E.; Stevens, J.; Lane, W. J.; Javeri, I. An Immunogenic Personal Neoantigen Vaccine for Patients with Melanoma. Nature 2017, 547, 217– 221,  DOI: 10.1038/nature22991
    Google Scholar
    26
    An immunogenic personal neoantigen vaccine for patients with melanoma
    Ott, Patrick A.; Hu, Zhuting; Keskin, Derin B.; Shukla, Sachet A.; Sun, Jing; Bozym, David J.; Zhang, Wandi; Luoma, Adrienne; Giobbie-Hurder, Anita; Peter, Lauren; Chen, Christina; Olive, Oriol; Carter, Todd A.; Li, Shuqiang; Lieb, David J.; Eisenhaure, Thomas; Gjini, Evisa; Stevens, Jonathan; Lane, William J.; Javeri, Indu; Nellaiappan, Kaliappanadar; Salazar, Andres M.; Daley, Heather; Seaman, Michael; Buchbinder, Elizabeth I.; Yoon, Charles H.; Harden, Maegan; Lennon, Niall; Gabriel, Stacey; Rodig, Scott J.; Barouch, Dan H.; Aster, Jon C.; Getz, Gad; Wucherpfennig, Kai; Neuberg, Donna; Ritz, Jerome; Lander, Eric S.; Fritsch, Edward F.; Hacohen, Nir; Wu, Catherine J.
    Nature (London, United Kingdom) (2017), 547 (7662), 217-221CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Effective anti-tumor immunity in humans has been assocd. with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumor-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumor immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumors, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) mols. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoral balance in favor of enhanced tumor control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumor neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, resp. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumor. Of six vaccinated patients, four had no recurrence at 25 mo after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumor regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFaqt7rO&md5=e235523b95d4f6ae4aeceb1047460ab3
  27. 27
    Swartz, M. A.; Hirosue, S.; Hubbell, J. A. Engineering Approaches to Immunotherapy. Science Translational Medicine 2012, 4, 148rv149,  DOI: 10.1126/scitranslmed.3003763
    Google Scholar
    There is no corresponding record for this reference.
  28. 28
    Knight, F. C.; Gilchuk, P.; Kumar, A.; Becker, K. W.; Sevimli, S.; Jacobson, M. E.; Suryadevara, N.; Wang-Bishop, L.; Boyd, K. L.; Crowe, J. E., Jr.; Joyce, S.; Wilson, J. T. Mucosal Immunization with a pH-Responsive Nanoparticle Vaccine Induces Protective CD8(+) Lung-Resident Memory T Cells. ACS Nano 2019, 13, 10939– 10960,  DOI: 10.1021/acsnano.9b00326
    Google Scholar
    28
    Mucosal Immunization with a pH-Responsive Nanoparticle Vaccine Induces Protective CD8+ Lung-Resident Memory T Cells
    Knight, Frances C.; Gilchuk, Pavlo; Kumar, Amrendra; Becker, Kyle W.; Sevimli, Sema; Jacobson, Max E.; Suryadevara, Naveenchandra; Wang-Bishop, Lihong; Boyd, Kelli L.; Crowe, James E.; Joyce, Sebastian; Wilson, John T.
    ACS Nano (2019), 13 (10), 10939-10960CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Tissue-resident memory T cells (TRM) patrol nonlymphoid organs and provide superior protection against pathogens that commonly infect mucosal and barrier tissues, such as the lungs, intestine, liver, and skin. Thus, there is a need for vaccine technologies that can induce a robust, protective TRM response in these tissues. Nanoparticle (NP) vaccines offer important advantages over conventional vaccines; however, there has been minimal investigation into the design of NP-based vaccines for eliciting TRM responses. Here, we describe a pH-responsive polymeric nanoparticle vaccine for generating antigen-specific CD8+ TRM cells in the lungs. With a single intranasal dose, the NP vaccine elicited airway- and lung-resident CD8+ TRM cells and protected against respiratory virus challenge in both sublethal (vaccinia) and lethal (influenza) infection models for up to 9 wk after immunization. In elucidating the contribution of material properties to the resulting TRM response, we found that the pH-responsive activity of the carrier was important, as a structurally analogous non-pH-responsive control carrier elicited significantly fewer lung-resident CD8+ T cells. We also demonstrated that dual-delivery of protein antigen and nucleic acid adjuvant on the same NP substantially enhanced the magnitude, functionality, and longevity of the antigen-specific CD8+ TRM response in the lungs. Compared to administration of sol. antigen and adjuvant, the NP also mediated retention of vaccine cargo in pulmonary antigen-presenting cells (APCs), enhanced APC activation, and increased prodn. of TRM-related cytokines. Overall, these data suggest a promising vaccine platform technol. for rapid generation of protective CD8+ TRM cells in the lungs.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVCnt7%252FO&md5=44662b0a177490dcb700c98b7fd56e5e
  29. 29
    Kuai, R.; Ochyl, L. J.; Bahjat, K. S.; Schwendeman, A.; Moon, J. J. Designer Vaccine Nanodiscs for Personalized Cancer Immunotherapy. Nat. Mater. 2017, 16, 489– 496,  DOI: 10.1038/nmat4822
    Google Scholar
    29
    Designer vaccine nanodiscs for personalized cancer immunotherapy
    Kuai, Rui; Ochyl, Lukasz J.; Bahjat, Keith S.; Schwendeman, Anna; Moon, James J.
    Nature Materials (2017), 16 (4), 489-496CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
    Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumor exome sequencing have signalled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodol. for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high-d. lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than sol. vaccines and even 31-fold greater than perhaps the strongest adjuvant in clin. trials (i.e., CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumor growth. Nanodiscs eliminated established MC-38 and B16F10 tumors when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFGitLvO&md5=247bc6ef1a21f3a1bce8addcbb7a6a0d
  30. 30
    Li, A. W.; Sobral, M. C.; Badrinath, S.; Choi, Y.; Graveline, A.; Stafford, A. G.; Weaver, J. C.; Dellacherie, M. O.; Shih, T. Y.; Ali, O. A.; Kim, J.; Wucherpfennig, K. W.; Mooney, D. J. A Facile Approach to Enhance Antigen Response for Personalized Cancer Vaccination. Nat. Mater. 2018, 17, 528– 534,  DOI: 10.1038/s41563-018-0028-2
    Google Scholar
    30
    A facile approach to enhance antigen response for personalized cancer vaccination
    Li, Aileen Weiwei; Sobral, Miguel C.; Badrinath, Soumya; Choi, Youngjin; Graveline, Amanda; Stafford, Alexander G.; Weaver, James C.; Dellacherie, Maxence O.; Shih, Ting-Yu; Ali, Omar A.; Kim, Jaeyun; Wucherpfennig, Kai W.; Mooney, David J.
    Nature Materials (2018), 17 (6), 528-534CODEN: NMAACR; ISSN:1476-1122. (Nature Research)
    Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations. Impressively, a single injection of the MSR-PEI vaccine using an E7 peptide completely eradicated large, established TC-1 tumors in about 80% of mice and generated immunol. memory. When immunized with a pool of B16F10 or CT26 neoantigens, the MSR-PEI vaccine eradicated established lung metastases, controlled tumor growth and synergized with anti-CTLA4 therapy. Our findings from three independent tumor models suggest that the MSR-PEI vaccine approach may serve as a facile and powerful multi-antigen platform to enable robust personalized cancer vaccination.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXltFOrsrs%253D&md5=3723b6388b35a6a546eb78ace8db9e9f
  31. 31
    Liu, H.; Moynihan, K. D.; Zheng, Y.; Szeto, G. L.; Li, A. V.; Huang, B.; Van Egeren, D. S.; Park, C.; Irvine, D. J. Structure-Based Programming of Lymph-Node Targeting in Molecular Vaccines. Nature 2014, 507, 519– 522,  DOI: 10.1038/nature12978
    Google Scholar
    31
    Structure-based programming of lymph-node targeting in molecular vaccines
    Liu, Haipeng; Moynihan, Kelly D.; Zheng, Yiran; Szeto, Gregory L.; Li, Adrienne V.; Huang, Bonnie; Van Egeren, Debra S.; Park, Clara; Irvine, Darrell J.
    Nature (London, United Kingdom) (2014), 507 (7493), 519-522CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compds. to LNs, where they are efficiently filtered by resident phagocytes. Here we translate this 'albumin hitchhiking' approach to mol. vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a soly.-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compds., leading to 30-fold increases in T-cell priming and enhanced anti-tumor efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvV2ru70%253D&md5=2890c3d27d8b989930052ba6bbed3294
  32. 32
    Lynn, G. M.; Sedlik, C.; Baharom, F.; Zhu, Y.; Ramirez-Valdez, R. A.; Coble, V. L.; Tobin, K.; Nichols, S. R.; Itzkowitz, Y.; Zaidi, N.; Gammon, J. M.; Blobel, N. J.; Denizeau, J.; de la Rochere, P.; Francica, B. J.; Decker, B.; Maciejewski, M.; Cheung, J.; Yamane, H.; Smelkinson, M. G. Peptide-TLR-7/8a Conjugate Vaccines Chemically Programmed for Nanoparticle Self-Assembly Enhance CD8 T-Cell Immunity to Tumor Antigens. Nat. Biotechnol. 2020, 38, 320– 332,  DOI: 10.1038/s41587-019-0390-x
    Google Scholar
    32
    Peptide-TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens
    Lynn, Geoffrey M.; Sedlik, Christine; Baharom, Faezzah; Zhu, Yaling; Ramirez-Valdez, Ramiro A.; Coble, Vincent L.; Tobin, Kennedy; Nichols, Sarah R.; Itzkowitz, Yaakov; Zaidi, Neeha; Gammon, Joshua M.; Blobel, Nicolas J.; Denizeau, Jordan; de la Rochere, Philippe; Francica, Brian J.; Decker, Brennan; Maciejewski, Mateusz; Cheung, Justin; Yamane, Hidehiro; Smelkinson, Margery G.; Francica, Joseph R.; Laga, Richard; Bernstock, Joshua D.; Seymour, Leonard W.; Drake, Charles G.; Jewell, Christopher M.; Lantz, Olivier; Piaggio, Eliane; Ishizuka, Andrew S.; Seder, Robert A.
    Nature Biotechnology (2020), 38 (3), 320-332CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
    Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochem. variability can present challenges to manufg. personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chem. programmed to self-assemble into nanoparticles of uniform size (∼20 nm) irresp. of the peptide antigen compn. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ∼50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXotFGltw%253D%253D&md5=2b4321aa1d0eec8e7a4b2d5aca33a648
  33. 33
    Shae, D.; Baljon, J. J.; Wehbe, M.; Christov, P. P.; Becker, K. W.; Kumar, A.; Suryadevara, N.; Carson, C. S.; Palmer, C. R.; Knight, F. C.; Joyce, S.; Wilson, J. T. Co-Delivery of Peptide Neoantigens and Stimulator of Interferon Genes Agonists Enhances Response to Cancer Vaccines. ACS Nano 2020, 14, 9904– 9916,  DOI: 10.1021/acsnano.0c02765
    Google Scholar
    33
    Co-delivery of Peptide Neoantigens and Stimulator of Interferon Genes Agonists Enhances Response to Cancer Vaccines
    Shae, Daniel; Baljon, Jessalyn J.; Wehbe, Mohamed; Christov, Plamen P.; Becker, Kyle W.; Kumar, Amrendra; Suryadevara, Naveenchandra; Carson, Carcia S.; Palmer, Christian R.; Knight, Frances C.; Joyce, Sebastian; Wilson, John T.
    ACS Nano (2020), 14 (8), 9904-9916CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Cancer vaccines targeting patient-specific neoantigens have emerged as a promising strategy for improving responses to immune checkpoint blockade. However, neoantigenic peptides are poorly immunogenic and inept at stimulating CD8+ T cell responses, motivating a need for new vaccine technologies that enhance their immunogenicity. The stimulator of interferon genes (STING) pathway is an endogenous mechanism by which the innate immune system generates an immunol. context for priming and mobilizing neoantigen-specific T cells. Owing to this crit. role in tumor immune surveillance, a synthetic cancer nanovaccine platform (nanoSTING-vax) was developed that mimics immunogenic cancer cells in its capacity to efficiently promote co-delivery of peptide antigens and the STING agonist, cGAMP. The co-loading of cGAMP and peptides into pH-responsive, endosomolytic polymersomes promoted the coordinated delivery of both cGAMP and peptide antigens to the cytosol, thereby eliciting inflammatory cytokine prodn., co-stimulatory marker expression, and antigen cross-presentation. Consequently, nanoSTING-vax significantly enhanced CD8+ T cell responses to a range of peptide antigens. Therapeutic immunization with nanoSTING-vax, in combination with immune checkpoint blockade, inhibited tumor growth in multiple murine tumor models, even leading to complete tumor rejection and generation of durable antitumor immune memory. Collectively, this work establishes nanoSTING-vax as a versatile platform for enhancing immune responses to neoantigen-targeted cancer vaccines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVCmsLjL&md5=e52e9db129f9916ccbb51b96ead541fc
  34. 34
    Tornesello, A. L.; Tagliamonte, M.; Tornesello, M. L.; Buonaguro, F. M.; Buonaguro, L. Nanoparticles to Improve the Efficacy of Peptide-Based Cancer Vaccines. Cancers (Basel) 2020, 12, 1049,  DOI: 10.3390/cancers12041049
    Google Scholar
    There is no corresponding record for this reference.
  35. 35
    Viswanath, D. I.; Liu, H. C.; Huston, D. P.; Chua, C. Y. X.; Grattoni, A. Emerging Biomaterial-Based Strategies for Personalized Therapeutic in Situ Cancer Vaccines. Biomaterials 2022, 280, 121297,  DOI: 10.1016/j.biomaterials.2021.121297
    Google Scholar
    35
    Emerging biomaterial-based strategies for personalized therapeutic in situ cancer vaccines
    Viswanath, Dixita Ishani; Liu, Hsuan-Chen; Huston, David P.; Chua, Corrine Ying Xuan; Grattoni, Alessandro
    Biomaterials (2022), 280 (), 121297CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    A review. Landmark successes in oncoimmunol. have led to development of therapeutics boosting the host immune system to eradicate local and distant tumors with impactful tumor redn. in a subset of patients. However, current immunotherapy modalities often demonstrate limited success when involving immunol. cold tumors and solid tumors. Here, we describe the role of various biomaterials to formulate cancer vaccines as a form of cancer immunotherapy, seeking to utilize the host immune system to activate and expand tumor-specific T cells. Biomaterial-based cancer vaccines enhance the cancer-immunity cycle by harnessing cellular recruitment and activation against tumor-specific antigens. In this review, we discuss biomaterial-based vaccine strategies to induce lymphocytic responses necessary to mediate anti-tumor immunity. We focus on strategies that selectively attract dendritic cells via immunostimulatory gradients, activate them against presented tumor-specific antigens, and induce effective cross-presentation to T cells in secondary lymphoid organs, thereby generating immunity. We posit that personalized cancer vaccines are promising targets to generate long-term systemic immunity against patient- and tumor-specific antigens to ensure long-term cancer remission.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXislWkurfI&md5=6c16a058af7c31ba986ce1a85033ee82
  36. 36
    Wu, S.; Xia, Y.; Hu, Y.; Ma, G. Bio-Mimic Particles for the Enhanced Vaccinations: Lessons Learnt from the Natural Traits and Pathogenic Invasion. Adv. Drug Deliv Rev. 2021, 176, 113871,  DOI: 10.1016/j.addr.2021.113871
    Google Scholar
    36
    Bio-mimic particles for the enhanced vaccinations: Lessons learnt from the natural traits and pathogenic invasion
    Wu, Sihua; Xia, Yufei; Hu, Yuning; Ma, Guanghui
    Advanced Drug Delivery Reviews (2021), 176 (), 113871CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    A review. In the combat against pathogens, the immune systems were evolved with the immune recognitions against the various danger signals, which responded vigorously upon the pathogen invasions and elicited potent antibodies or T cell engagement against the re-infections. Envisage with the prevailing pandemics and increasing demands for cancer vaccines, bio-mimic particles were developed to imitate the natural traits of the pathogens, which conferred the optimal strategies to stimulate the immune engagement and let to the increased vaccine efficacy. Here, the recent development in bio-mimic particles, as well as the natural cues from the pathogens were discussed. As such, the designing principles that adapted from the physiochem. properties of the pathogens were unfolded as the surface characteristics (hydrophobic, nano-pattern, antigen display, charge), properties (size, shape, softness) and the delivered components (peptide, protein, nuclear acids, toll-like receptor (TLR) agonist, antibody). Addnl., the strategies for the efficient delivery, regarding the biodistribution, internalization and presentation of the antigens were also illustrated. Through reviewing the state-of-art in biomimetic particles, the lesson learnt from the natural traits and pathogenic invasion may shed light on the rational design for the enhanced vaccinations.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1KgsL7O&md5=106fa4408f1ebb0c26ae41f4a4c8df36
  37. 37
    Rosenthal, J. A.; Chen, L.; Baker, J. L.; Putnam, D.; DeLisa, M. P. Pathogen-Like Particles: Biomimetic Vaccine Carriers Engineered at the Nanoscale. Curr. Opin Biotechnol 2014, 28, 51– 58,  DOI: 10.1016/j.copbio.2013.11.005
    Google Scholar
    37
    Pathogen-like particles: biomimetic vaccine carriers engineered at the nanoscale
    Rosenthal, Joseph A.; Chen, Linxiao; Baker, Jenny L.; Putnam, David; DeLisa, Matthew P.
    Current Opinion in Biotechnology (2014), 28 (), 51-58CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
    Vaccine adjuvants are an essential component of vaccine design, helping to generate immunity to pathogen antigens in the absence of infection. Recent advances in nanoscale engineering have created a new class of particulate bionanotechnol. that uses biomimicry to better integrate adjuvant and antigen. These pathogen-like particles, or PLPs, can come from a variety of sources, ranging from fully synthetic platforms to biol. derived, self-assembling systems. By employing molecularly engineered targeting and stimulation of key immune cells, recent studies utilizing PLPs as vaccine delivery platforms have shown great promise against high-impact, unsolved vaccine targets ranging from bacterial and viral pathogens to cancer and addiction.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtF2ktLfK&md5=e2b314a29050e3a7f370dcf0137aa250
  38. 38
    Gutjahr, A.; Papagno, L.; Nicoli, F.; Kanuma, T.; Kuse, N.; Cabral-Piccin, M. P.; Rochereau, N.; Gostick, E.; Lioux, T.; Perouzel, E. The STING Ligand cGamp Potentiates the Efficacy of Vaccine-Induced CD8+ T Cells. JCI Insight 2019, 4 (7), e125107,  DOI: 10.1172/jci.insight.125107
    Google Scholar
    There is no corresponding record for this reference.
  39. 39
    He, Y.; Hong, C.; Fletcher, S. J.; Berger, A. G.; Sun, X.; Yang, M.; Huang, S.; Belcher, A. M.; Irvine, D. J.; Li, J.; Hammond, P. T. Peptide-Based Cancer Vaccine Delivery Via the STINGΔTM-cGamp Complex. Adv. Healthc Mater. 2022, 11, e2200905  DOI: 10.1002/adhm.202200905
    Google Scholar
    39
    Peptide-Based Cancer Vaccine Delivery via the STINGΔTM-cGAMP Complex
    He, Yanpu; Hong, Celestine; Fletcher, Samantha J.; Berger, Adam G.; Sun, Xin; Yang, Mengdi; Huang, Shengnan; Belcher, Angela M.; Irvine, Darrell J.; Li, Jiahe; Hammond, Paula T.
    Advanced Healthcare Materials (2022), 11 (15), 2200905CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)
    With the advent of bioinformatic tools in efficiently predicting neo-antigens, peptide vaccines have gained tremendous attention in cancer immunotherapy. However, the delivery of peptide vaccines remains a major challenge, primarily due to ineffective transport to lymph nodes and low immunogenicity. Here, a strategy for peptide vaccine delivery is reported by first fusing the peptide to the cytosolic domain of the stimulator of interferon genes protein (STINGΔTM), then complexing the peptide-STINGΔTM protein with STING agonist 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The process results in the formation of self-assembled cGAMP-peptide-STINGΔTM tetramers, which enables efficient lymphatic trafficking of the peptide. Moreover, the cGAMP-STINGΔTM complex acts not only as a protein carrier for the peptide, but also as a potent adjuvant capable of triggering STING signaling independent of endogenous STING protein-an esp. important attribute considering that certain cancer cells epigenetically silence their endogenous STING expression. With model antigen SIINFEKL, it is demonstrated that the platform elicits effective STING signaling in vitro, draining lymph node targeting in vivo, effective T cell priming in vivo as well as antitumoral immune response in a mouse colon carcinoma model, providing a versatile soln. to the challenges faced in peptide vaccine delivery.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsFGqt7jK&md5=48caf8a595d73d5693dcfc610067baf7
  40. 40
    Li, X. D.; Wu, J.; Gao, D.; Wang, H.; Sun, L.; Chen, Z. J. Pivotal Roles of cGAS-cGAMP Signaling in Antiviral Defense and Immune Adjuvant Effects. Science 2013, 341, 1390– 1394,  DOI: 10.1126/science.1244040
    Google Scholar
    40
    Pivotal Roles of cGAS-cGAMP Signaling in Antiviral Defense and Immune Adjuvant Effects
    Li, Xiao-Dong; Wu, Jiaxi; Gao, Daxing; Wang, Hua; Sun, Lijun; Chen, Zhijian J.
    Science (Washington, DC, United States) (2013), 341 (6152), 1390-1394CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Invasion of microbial DNA into the cytoplasm of animal cells triggers a cascade of host immune reactions that help clear the infection; however, self DNA in the cytoplasm can cause autoimmune diseases. Biochem. approaches led to the identification of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) as a cytosolic DNA sensor that triggers innate immune responses. Here, we show that cells from cGAS-deficient (cGas-/-) mice, including fibroblasts, macrophages, and dendritic cells, failed to produce type I interferons and other cytokines in response to DNA transfection or DNA virus infection. cGas-/- mice were more susceptible to lethal infection with herpes simplex virus 1 (HSV1) than wild-type mice. We also show that cGAMP is an adjuvant that boosts antigen-specific T cell activation and antibody prodn. in mice.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVCmu7vK&md5=46c48534439d7b6442911d63f7c3fa51
  41. 41
    Van Herck, S.; Feng, B.; Tang, L. Delivery of STING Agonists for Adjuvanting Subunit Vaccines. Adv. Drug Deliv Rev. 2021, 179, 114020,  DOI: 10.1016/j.addr.2021.114020
    Google Scholar
    41
    Delivery of STING agonists for adjuvanting subunit vaccines
    Van Herck, Simon; Feng, Bing; Tang, Li
    Advanced Drug Delivery Reviews (2021), 179 (), 114020CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
    A review. Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the immunogenicity and efficacy of vaccines. Recently discovered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has attracted much attention as it is a key mediator for modulating immune responses. Vaccines adjuvanted with STING agonists are found to mediate a robust immune defense against infections and cancer. In this review, we first discuss the mechanisms of STING agonists in the context of vaccination. Next, we present recent progress in novel STING agonist discovery and the delivery strategies. We next highlight recent work in optimizing the efficacy while minimizing toxicity of STING agonist-assisted subunit vaccines for protection against infectious diseases or treatment of cancer. Finally, we share our perspectives of current issues and future directions in further developing STING agonists for adjuvanting subunit vaccines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVyrsrnM&md5=991bac587ff443dcb8ebbbdef18d31ae
  42. 42
    Embgenbroich, M.; Burgdorf, S. Current Concepts of Antigen Cross-Presentation. Front Immunol 2018, 9, 1643,  DOI: 10.3389/fimmu.2018.01643
    Google Scholar
    42
    Current concepts of antigen cross-presentation
    Embgenbroich, Maria; Burgdorf, Sven
    Frontiers in Immunology (2018), 9 (), 1643/1-1643/10CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    Dendritic cells have the ability to efficiently present internalized antigens on major histocompatibility complex (MHC) I mols. This process is termed cross-presentation and is important role in the generation of an immune response against viruses and tumors, after vaccinations or in the induction of immune tolerance. The mol. mechanisms enabling cross-presentation have been topic of intense debate since many years. However, a clear view on these mechanisms remains difficult, partially due to important remaining questions, controversial results and discussions. Here, we give an overview of the current concepts of antigen cross-presentation and focus on a description of the major cross-presentation pathways, the role of retarded antigen degrdn. for efficient cross-presentation, the dislocation of antigens from endosomal compartment into the cytosol, the reverse transport of proteasome-derived peptides for loading on MHC I and the translocation of the cross-presentation machinery from the ER to endosomes. We try to highlight recent advances, discuss some of the controversial data and point out some of the major open questions in the field.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlSisLvP&md5=c6d5b139383717e9d5ed31dafc8a55d3
  43. 43
    Tom, J. K.; Albin, T. J.; Manna, S.; Moser, B. A.; Steinhardt, R. C.; Esser-Kahn, A. P. Applications of Immunomodulatory Immune Synergies to Adjuvant Discovery and Vaccine Development. Trends Biotechnol 2019, 37, 373– 388,  DOI: 10.1016/j.tibtech.2018.10.004
    Google Scholar
    43
    Applications of Immunomodulatory Immune Synergies to Adjuvant Discovery and Vaccine Development
    Tom, Janine K.; Albin, Tyler J.; Manna, Saikat; Moser, Brittany A.; Steinhardt, Rachel C.; Esser-Kahn, Aaron P.
    Trends in Biotechnology (2019), 37 (4), 373-388CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
    A review. Pathogens comprise a diverse set of immunostimulatory mols. that activate the innate immune system during infection. The immune system recognizes distinct combinations of pathogenic mols. leading to multiple immune activation events that cooperate to produce enhanced immune responses, known as 'immune synergies'. Effective immune synergies are essential for the clearance of pathogens, thus inspiring novel adjuvant design to improve vaccines. We highlight current vaccine adjuvants and the importance of immune synergies to adjuvant and vaccine design. The focus is on new technologies used to study and apply immune synergies to adjuvant and vaccine development. Finally, we discuss how recent findings can be applied to the future design and characterization of synergistic adjuvants and vaccines.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2itbrN&md5=c5510e87652758ab52910904679d93f2
  44. 44
    Collier, M. A.; Junkins, R. D.; Gallovic, M. D.; Johnson, B. M.; Johnson, M. M.; Macintyre, A. N.; Sempowski, G. D.; Bachelder, E. M.; Ting, J. P.; Ainslie, K. M. Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists. Mol. Pharmaceutics 2018, 15, 4933– 4946,  DOI: 10.1021/acs.molpharmaceut.8b00579
    Google Scholar
    44
    Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists
    Collier, Michael A.; Junkins, Robert D.; Gallovic, Matthew D.; Johnson, Brandon M.; Johnson, Monica M.; Macintyre, Andrew N.; Sempowski, Gregory D.; Bachelder, Eric M.; Ting, Jenny P.-Y.; Ainslie, Kristy M.
    Molecular Pharmaceutics (2018), 15 (11), 4933-4946CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Vaccines are the most effective tool for preventing infectious diseases; however, subunit vaccines, considered the safest type, suffer from poor immunogenicity and require adjuvants to create a strong and sustained immune response. As adjuvants, pathogen-assocd. mol. patterns (PAMPs) offer potent immunostimulatory properties and defined mechanisms of action through their cognate pattern recognition receptors (PRRs). Their activity can be further enhanced through combining two or more PAMPs, particularly those that activate multiple immune signaling pathways. However, the cytosolic localization of many PRRs requires intracellular delivery of PAMPs for optimal biol. activity, which is particularly true of the stimulator of interferon genes (STING) PRR. Using acetalated dextran (Ace-DEX) microparticles (MPs) encapsulating STING agonist 3'3'-cyclic GMP-AMP (cGAMP) combined with sol. PAMPS, we screened the effect of codelivery of adjuvants using primary mouse bone marrow derived dendritic cells (BMDCs). We identified that codelivery of cGAMP MPs and sol. Toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) elicited the broadest cytokine response. CGAMP and R848 were then coencapsulated within Ace-DEX MPs via electrospray. Using the model antigen ovalbumin, we obsd. that Ace-DEX MPs coencapsulating cGAMP and R848 (cGAMP/R848 Ace-DEX MPs) induced antigen-specific cellular immunity, and a balanced Th1/Th2 humoral response that was greater than cGAMP Ace-DEX MPs alone and PAMPs delivered in sep. MPs. These data indicate that polymeric Ace-DEX MPs loaded with STING and TLR7/8 agonists represent a potent cellular and humoral vaccine adjuvant.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVertLvM&md5=72cfae51f29f59ae7c4a6b11a36d7acb
  45. 45
    Barman, S.; Borriello, F.; Brook, B.; Pietrasanta, C.; De Leon, M.; Sweitzer, C.; Menon, M.; van Haren, S. D.; Soni, D.; Saito, Y.; Nanishi, E.; Yi, S.; Bobbala, S.; Levy, O.; Scott, E. A.; Dowling, D. J. Shaping Neonatal Immunization by Tuning the Delivery of Synergistic Adjuvants Via Nanocarriers. ACS Chem. Biol. 2022, 17, 2559– 2571,  DOI: 10.1021/acschembio.2c00497
    Google Scholar
    45
    Shaping Neonatal Immunization by Tuning the Delivery of Synergistic Adjuvants via Nanocarriers
    Barman, Soumik; Borriello, Francesco; Brook, Byron; Pietrasanta, Carlo; De Leon, Maria; Sweitzer, Cali; Menon, Manisha; van Haren, Simon D.; Soni, Dheeraj; Saito, Yoshine; Nanishi, Etsuro; Yi, Sijia; Bobbala, Sharan; Levy, Ofer; Scott, Evan A.; Dowling, David J.
    ACS Chemical Biology (2022), 17 (9), 2559-2571CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    Adjuvanted nanocarrier-based vaccines hold substantial potential for applications in novel early-life immunization strategies. Here, via mouse and human age-specific in vitro modeling, we identified the combination of a small-mol. STING agonist (2'3'-cyclic GMP-AMP, cGAMP) and a TLR7/8 agonist (CL075) to drive the synergistic activation of neonatal dendritic cells and precision CD4 T-helper (Th) cell expansion via the IL-12/IFNγ axis. We further demonstrate that the vaccination of neonatal mice with quadrivalent influenza recombinant hemagglutinin (rHA) and an admixt. of two polymersome (PS) nanocarriers sep. encapsulating cGAMP (cGAMP-PS) and CL075 (CL075-PS) drove robust Th1 bias, high frequency of T follicular helper (TFH) cells, and germinal center (GC) B cells along with the IgG2c-skewed humoral response in vivo. Dual-loaded cGAMP/CL075-PSs did not outperform admixed cGAMP-PS and CL075-PS in vivo. These data validate an optimally designed adjuvantation system via age-selected small-mol. synergy and a multicomponent nanocarrier formulation as an effective approach to induce type 1 immune responses in early life.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xit1alsb3K&md5=779648f1160a984f3c8b7b98026bf77c
  46. 46
    Kuai, R.; Sun, X.; Yuan, W.; Ochyl, L. J.; Xu, Y.; Hassani Najafabadi, A.; Scheetz, L.; Yu, M. Z.; Balwani, I.; Schwendeman, A.; Moon, J. J. Dual TLR Agonist Nanodiscs as a Strong Adjuvant System for Vaccines and Immunotherapy. J. Controlled Release 2018, 282, 131– 139,  DOI: 10.1016/j.jconrel.2018.04.041
    Google Scholar
    46
    Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy
    Kuai, Rui; Sun, Xiaoqi; Yuan, Wenmin; Ochyl, Lukasz J.; Xu, Yao; Hassani Najafabadi, Alireza; Scheetz, Lindsay; Yu, Min-Zhi; Balwani, Ishina; Schwendeman, Anna; Moon, James J.
    Journal of Controlled Release (2018), 282 (), 131-139CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    Recent studies have shown that certain combinations of Toll-like receptor (TLR) agonists can induce synergistic immune activation. However, it remains challenging to achieve such robust responses in vivo in a manner that is effective, facile, and amenable for clin. translation. Here, we show that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-d. lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides. ND-MPLA/CpG significantly enhanced activation of dendritic cells, compared with free dual adjuvants or nanodiscs delivering a single TLR agonist. Importantly, mice immunized with phys. mixts. of protein antigens ND-MPLA/CpG generated strong humoral responses, including induction of IgG responses against protein convertase subtilisin/kexin 9 (PCSK9), leading to 17-30% redn. of the total plasma cholesterol levels. Moreover, ND-MPLA/CpG exerted strong anti-tumor efficacy in multiple murine tumor models. Compared with free adjuvants, ND-MPLA/CpG admixed with ovalbumin markedly improved antigen-specific CD8+ T cell responses by 8-fold and promoted regression of B16F10-OVA melanoma (P<0.0001). Furthermore, ND-MPLA/CpG admixed with E7 peptide antigen elicited ∼20% E7-specific CD8+ T cell responses and achieved complete regression of established TC-1 tumors in all treated animals. Taken together, our work highlights the simplicity, versatility, and potency of dual TLR agonist nanodiscs for applications in vaccines and cancer immunotherapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFWrtr0%253D&md5=00b84399e940517a6e19c016bd9fc318
  47. 47
    Zhang, B. D.; Wu, J. J.; Li, W. H.; Hu, H. G.; Zhao, L.; He, P. Y.; Zhao, Y. F.; Li, Y. M. STING and TLR7/8 Agonists-Based Nanovaccines for Synergistic Antitumor Immune Activation. Nano Res. 2022, 15, 6328– 6339,  DOI: 10.1007/s12274-022-4282-x
    Google Scholar
    47
    STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation
    Zhang, Bo-Dou; Wu, Jun-Jun; Li, Wen-Hao; Hu, Hong-Guo; Zhao, Lang; He, Pei-Yang; Zhao, Yu-Fen; Li, Yan-Mei
    Nano Research (2022), 15 (7), 6328-6339CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)
    Immunostimulatory therapies based on pattern recognition receptors (PRRs) have emerged as an effective approach in the fight against cancer, with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment. The agonist cyclic dinucleotides (CDNs) of the stimulator of interferon gene (STING) are a group of very promising anticancer mols. that increase tumor immunogenicity by activating innate immunity. However, the tumor immune efficacy of CDNs is limited by several factors, including relatively narrow cytokine prodn., inefficient delivery to STING, and rapid clearance. In addn., a single adjuvant mol. is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect. To address this problem, two or more agonist mols. are often used together to synergistically enhance immune efficacy. In this work, we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8 (TLR7/8) agonist 522 produced a broader cytokine response. Subsequently, we developed multicomponent nanovaccines (MCNVs) consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant mols. These MCNVs activate bone marrow-derived dendritic cells (BMDCs) to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor T-cell responses. In in vivo expts., we obsd. that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes, resulting in significant tumor regression and, notably, a 100% survival rate in mice through 25 days without other partnering therapies. These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhtVeitLbO&md5=0103b8d2efebe7669675a9d6ee1e51b5
  48. 48
    Pradhan, P.; Toy, R.; Jhita, N.; Atalis, A.; Pandey, B.; Beach, A.; Blanchard, E. L.; Moore, S. G.; Gaul, D. A.; Santangelo, P. J. TRAF6-IRF5 Kinetics, TRIF, and Biophysical Factors Drive Synergistic Innate Responses to Particle-Mediated MPLA-CpG Co-Presentation. Sci. Adv. 2021, 7, abd4235,  DOI: 10.1126/sciadv.abd4235
    Google Scholar
    There is no corresponding record for this reference.
  49. 49
    Temizoz, B.; Kuroda, E.; Ohata, K.; Jounai, N.; Ozasa, K.; Kobiyama, K.; Aoshi, T.; Ishii, K. J. TLR9 and STING Agonists Synergistically Induce Innate and Adaptive Type-II IFN. Eur. J. Immunol. 2015, 45, 1159– 1169,  DOI: 10.1002/eji.201445132
    Google Scholar
    49
    TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN
    Temizoz, Burcu; Kuroda, Etsushi; Ohata, Keiichi; Jounai, Nao; Ozasa, Koji; Kobiyama, Kouji; Aoshi, Taiki; Ishii, Ken J.
    European Journal of Immunology (2015), 45 (4), 1159-1169CODEN: EJIMAF; ISSN:0014-2980. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Agonists for TLR9 and Stimulator of IFN Gene (STING) act as vaccine adjuvants that induce type-1 immune responses. However, currently available CpG oligodeoxynucleotide (ODN) (K-type) induces IFNs only weakly and STING ligands rather induce type-2 immune responses, limiting their potential therapeutic applications. Here, we show a potent synergism between TLR9 and STING agonists. Together, they make an effective type-1 adjuvant and an anticancer agent. The synergistic effect between CpG ODN (K3) and STING-ligand cyclic GMP-AMP (cGAMP), culminating in NK cell IFN-γ (type-II IFN) prodn., is due to the concurrent effects of IL-12 and type-I IFNs, which are differentially regulated by IRF3/7, STING, and MyD88. The combination of CpG ODN with cGAMP is a potent type-1 adjuvant, capable of inducing strong Th1-type responses, as demonstrated by enhanced antigen-specific IgG2c and IFN-γ prodn., as well as cytotoxic CD8+ T-cell responses. In our murine tumor models, intratumoral injection of CpG ODN and cGAMP together reduced tumor size significantly compared with the singular treatments, acting as an antigen-free anticancer agent. Thus, the combination of CpG ODN and a STING ligand may offer therapeutic application as a potent type-II IFN inducer.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXks12gsr4%253D&md5=01e7129b3bc00d09165a64e1fa103859
  50. 50
    Kim, J. Y.; Rosenberger, M. G.; Chen, S.; Ip, C. K.; Bahmani, A.; Chen, Q.; Shen, J.; Tang, Y.; Wang, A.; Kenna, E.; Son, M.; Tay, S.; Ferguson, A. L.; Esser-Kahn, A. P. Discovery of New States of Immunomodulation for Vaccine Adjuvants Via High Throughput Screening: Expanding Innate Responses to PRRs. ACS Cent Sci. 2023, 9, 427– 439,  DOI: 10.1021/acscentsci.2c01351
    Google Scholar
    50
    Discovery of New States of Immunomodulation for Vaccine Adjuvants via High Throughput Screening: Expanding Innate Responses to PRRs
    Kim, Jeremiah Y.; Rosenberger, Matthew G.; Chen, Siquan; IP, Carman KM; Bahmani, Azadeh; Chen, Qing; Shen, Jinjing; Tang, Yifeng; Wang, Andrew; Kenna, Emma; Son, Minjun; Tay, Savas; Ferguson, Andrew L.; Esser-Kahn, Aaron P.
    ACS Central Science (2023), 9 (3), 427-439CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
    Stimulation of the innate immune system is crucial in both effective vaccinations and immunotherapies. This is often achieved through adjuvants, mols. that usually activate pattern recognition receptors (PRRs) and stimulate two innate immune signaling pathways: the nuclear factor kappa-light-chain-enhancer of activated B-cells pathway (NF-κB) and the interferon regulatory factors pathway (IRF). Here, we demonstrate the ability to alter and improve adjuvant activity via the addn. of small mol. "immunomodulators". By modulating signaling activity instead of receptor binding, these mols. allow the customization of select innate responses. We demonstrate both inhibition and enhancement of the products of the NF-κB and IRF pathways by several orders of magnitude. Some modulators apply generally across many receptors, while others focus specifically on individual receptors. Modulators boost correlates of a protective immune responses in a com. flu vaccine model and reduced correlates of reactogenicity in a typhoid vaccine model. These modulators have a range of applications: from adjuvanticity in prophylactics to enhancement of immunotherapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXjs1ygtb4%253D&md5=b2ef1701e544feba43084f5fc8b5d3ad
  51. 51
    Nihesh, N.; Manna, S.; Studnitzer, B.; Shen, J.; Esser-Kahn, A. P. A Synthetic Pathogen Mimetic Molecule Induces a Highly Amplified Synergistic Immune Response Via Activation of Multiple Signaling Pathways. Chem. Sci. 2021, 12, 6646– 6651,  DOI: 10.1039/D1SC00964H
    Google Scholar
    51
    A synthetic pathogen mimetic molecule induces a highly amplified synergistic immune response via activation of multiple signaling pathways
    Nihesh, Naorem; Manna, Saikat; Studnitzer, Bradley; Shen, Jingjing; Esser-Kahn, Aaron P.
    Chemical Science (2021), 12 (19), 6646-6651CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    The current understanding of how the immune system processes complex information during natural infections is yet to be exploited for the mol. design of potent immune activators. Here, we address this challenge by design of a pathogen-mimetic mol. that simultaneously co-activates cell-surface active, endosomal and cytosolic immune receptors.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXnvVGitr8%253D&md5=26cbbad0fab4671e7767affb9acdd81a
  52. 52
    Taylor, D.; Meyer, C. T.; Graves, D.; Sen, R.; Fu, J.; Tran, E.; Mirza, B.; Rodriguez, G.; Lang, C.; Feng, H.; Quaranta, V.; Wilson, J. T.; Kim, Y. J.; Korrer, M. J. MuSyC Dosing of Adjuvanted Cancer Vaccines Optimizes Antitumor Responses. Front Immunol 2022, 13, 936129,  DOI: 10.3389/fimmu.2022.936129
    Google Scholar
    52
    MuSyC dosing of adjuvanted cancer vaccines optimizes antitumor responses
    Taylor, David; Meyer, Christian T.; Graves, Diana; Sen, Rupashree; Fu, Juan; Tran, Emily; Mirza, Bilal; Rodriguez, Gabriel; Lang, Cara; Feng, Hanwen; Quaranta, Vito; Wilson, John T.; Kim, Young J.; Korrer, Michael J.
    Frontiers in Immunology (2022), 13 (), 936129CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    With the clin. approval of T-cell-dependent immune checkpoint inhibitors for many cancers, therapeutic cancer vaccines have re-emerged as a promising immunotherapy. Cancer vaccines require the addn. of immunostimulatory adjuvants to increase vaccine immunogenicity, and increasingly multiple adjuvants are used in combination to bolster further and shape cellular immunity to tumor antigens. However, rigorous quantification of adjuvants' synergistic interactions is challenging due to partial redundancy in costimulatory mols. and cytokine prodn., leading to the common assumption that combining both adjuvants at the max. tolerated dose results in optimal efficacy. Herein, we examine this max. dose assumption and find combinations of these doses are suboptimal. Instead, we optimized dendritic cell activation by extending the Multidimensional Synergy of Combinations (MuSyC) framework that measures the synergy of efficacy and potency between two vaccine adjuvants. Initially, we performed a preliminary in vitro screening of clin. translatable adjuvant receptor targets (TLR, STING, NLL, and RIG-I). We detd. that STING agonist (CDN) plus TLR4 agonist (MPL-A) or TLR7/8 agonist (R848) as the best pairwise combinations for dendritic cell activation. In addn., we found that the combination of R848 and CDN is synergistically efficacious and potent in activating both murine and human antigen-presenting cells (APCs) in vitro. These two selected adjuvants were then used to est. a MuSyC-dose optimized for in vivo T-cell priming using ovalbumin-based peptide vaccines. Finally, using B16 melanoma and MOC1 head and neck cancer models, MuSyC-dose-based adjuvating of cancer vaccines improved the antitumor response, increased tumor infiltrating lymphocytes, and induced novel myeloid tumor infiltration changes. Further, the MuSyC-dose-based adjuvants approach did not cause addnl. wt. changes or increased plasma cytokine levels compared to CDN alone. Collectively, our findings offer a proof of principle that our MuSyC-extended approach can be used to optimize cancer vaccine formulations for immunotherapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitlChu73M&md5=4f4dfbaf0362bfb299001faff278e0f6
  53. 53
    Hanson, M. C.; Crespo, M. P.; Abraham, W.; Moynihan, K. D.; Szeto, G. L.; Chen, S. H.; Melo, M. B.; Mueller, S.; Irvine, D. J. Nanoparticulate STING Agonists Are Potent Lymph Node-Targeted Vaccine Adjuvants. J. Clin Invest 2015, 125, 2532– 2546,  DOI: 10.1172/JCI79915
    Google Scholar
    53
    Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants
    Hanson Melissa C; Crespo Monica P; Abraham Wuhbet; Moynihan Kelly D; Szeto Gregory L; Chen Stephanie H; Melo Mariane B; Mueller Stefanie; Irvine Darrell J
    The Journal of clinical investigation (2015), 125 (6), 2532-46 ISSN:.
    Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfgsVChtw%253D%253D&md5=b840cee3cc090db0b723072b6936b05c
  54. 54
    Atukorale, P. U.; Raghunathan, S. P.; Raguveer, V.; Moon, T. J.; Zheng, C.; Bielecki, P. A.; Wiese, M. L.; Goldberg, A. L.; Covarrubias, G.; Hoimes, C. J.; Karathanasis, E. Nanoparticle Encapsulation of Synergistic Immune Agonists Enables Systemic Codelivery to Tumor Sites and IFNβ-Driven Antitumor Immunity. Cancer Res. 2019, 79, 5394– 5406,  DOI: 10.1158/0008-5472.CAN-19-0381
    Google Scholar
    54
    Nanoparticle encapsulation of synergistic immune agonists enables systemic codelivery to tumor sites and IFNβ-driven antitumor immunity
    Atukorale, Prabhani U.; Raghunathan, Shruti P.; Raguveer, Vanitha; Moon, Tayior J.; Zheng, Carolyn; Bielecki, Peter A.; Wiese, Michelle L.; Goldberg, Amy L.; Covarrubias, Gil; Hoimes, Christopher J.; Karathanasis, Efstathios
    Cancer Research (2019), 79 (20), 5394-5406CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    Effective cancer immunotherapy depends on the robust activation of tumor-specific antigen-presenting cells (APC). Immune agonists encapsulated within nanoparticles (NP) can be delivered to tumor sites to generate powerful antitumor immune responses with minimal off-target dissemination. Systemic delivery enables widespread access to the microvasculature and draining to the APC-rich perivasculature. We developed an immuno-nanoparticle (immuno-NP) coloaded with cyclic diguanylate monophosphate, an agonist of the stimulator of interferon genes pathway, and monophosphoryl lipid A, and a Toll-like receptor 4 agonist, which synergize to produce high levels of type I ΙΡΝβ. Usinga murine model of metastatic triple-neg. breast cancer. systemic delivery of these immuno-NPs resulted in significant therapeutic outcomes due to extensive upregulation of APCs and natural killer cells in the blood and tumor compared with control treatments. These results indicate that NPs can facilitate systemic delivery of multiple immune potentiating cargoes for effective APC-driven local and systemic antitumor immunity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFSqtb0%253D&md5=469de56cb58341e82e13aa77c48c6515
  55. 55
    Pandey, S.; Gruenbaum, A.; Kanashova, T.; Mertins, P.; Cluzel, P.; Chevrier, N. Pairwise Stimulations of Pathogen-Sensing Pathways Predict Immune Responses to Multi-Adjuvant Combinations. Cell Syst 2020, 11, 495– 508,  DOI: 10.1016/j.cels.2020.10.001
    Google Scholar
    55
    Pairwise Stimulations of Pathogen-Sensing Pathways Predict Immune Responses to Multi-adjuvant Combinations
    Pandey, Surya; Gruenbaum, Adam; Kanashova, Tamara; Mertins, Philipp; Cluzel, Philippe; Chevrier, Nicolas
    Cell Systems (2020), 11 (5), 495-508.e10CODEN: CSEYA4; ISSN:2405-4712. (Cell Press)
    The immune system makes decisions in response to combinations of multiple microbial inputs. We do not understand the combinatorial logic governing how higher-order combinations of microbial signals shape immune responses. Here, using coculture expts. and statistical analyses, we discover a general property for the combinatorial sensing of microbial signals, whereby the effects of triplet combinations of microbial signals on immune responses can be predicted by combining the effects of single and pairs. Mechanistically, we find that singles and pairs dictate the information signaled by triplets in mouse and human DCs at the levels of transcription, chromatin, and protein secretion. We exploit this simplifying property to develop cell-based immunotherapies prepd. with adjuvant combinations that trigger protective responses in mouse models of cancer. We conclude that the processing of multiple input signals by innate immune cells is governed by pairwise effects, which will inform the rationale combination of adjuvants to manipulate immunity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisVaqu7jK&md5=04738bf46febbbc04848669c0147be24
  56. 56
    Andrade, W. A.; Agarwal, S.; Mo, S.; Shaffer, S. A.; Dillard, J. P.; Schmidt, T.; Hornung, V.; Fitzgerald, K. A.; Kurt-Jones, E. A.; Golenbock, D. T. Type I Interferon Induction by Neisseria Gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-Like Receptor 4. Cell Rep 2016, 15, 2438– 2448,  DOI: 10.1016/j.celrep.2016.05.030
    Google Scholar
    56
    Type I Interferon Induction by Neisseriagonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4
    Andrade, Warrison A.; Agarwal, Sarika; Mo, Shunyan; Shaffer, Scott A.; Dillard, Joseph P.; Schmidt, Tobias; Hornung, Veit; Fitzgerald, Katherine A.; Kurt-Jones, Evelyn A.; Golenbock, Douglas T.
    Cell Reports (2016), 15 (11), 2438-2448CODEN: CREED8; ISSN:2211-1247. (Cell Press)
    The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) prodn. via TLR4/MD-2. In addn. to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2'3'-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression. Here, we reveal a cytosolic response to GC DNA that also contributes to type I IFN induction. We demonstrate that complete IFN-β induction by live GC depends on both cGAS and TLR4. Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS-/- and TLR4-/- cells. Collectively, these observations reveal cooperation between TLRs and cGAS in immunity to GC infection.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xpt1entbg%253D&md5=55421b21e0d3fce79cfbfe853151908d
  57. 57
    Kocabas, B. B.; Almacioglu, K.; Bulut, E. A.; Gucluler, G.; Tincer, G.; Bayik, D.; Gursel, M.; Gursel, I. Dual-Adjuvant Effect of pH-Sensitive Liposomes Loaded with STING and TLR9 Agonists Regress Tumor Development by Enhancing Th1 Immune Response. J. Controlled Release 2020, 328, 587– 595,  DOI: 10.1016/j.jconrel.2020.09.040
    Google Scholar
    57
    Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response
    Kocabas, Banu Bayyurt; Almacioglu, Kubra; Bulut, Esin Alpdundar; Gucluler, Gozde; Tincer, Gizem; Bayik, Defne; Gursel, Mayda; Gursel, Ihsan
    Journal of Controlled Release (2020), 328 (), 587-595CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    Nucleic acid-based pattern recognition receptor agonists are effective adjuvants and immunotherapeutic agents. Rather than single applications, ligand combinations could synergistically potentiate immune responses by elevating cytokine and chemokine prodn. via triggering multiple signaling pathways. However, short half-lives of such labile ligands due to nuclease attack and limited cellular uptake due to their structure significantly hamper their in vivo performances. More importantly, simultaneous delivery and activity presentation of protein antigen and nucleic acid ligands critically limit the clin. development of these constructs. In this work, we approached this problem by co-encapsulating a model antigen ovalbumin along with TLR9 and STING ligands within liposomes, a well-established drug delivery system that enables payload stability and enhanced cellular activity upon internalization. Moreover, by loading dual ligands we postulated to achieve heightened Th-1 immune response that would yield pronounced protective vaccine efficacy. We show that, pH-sensitive liposomes co-encapsulating CpG ODN and cGAMP induced synergistic innate immune response by elevating type I and type II interferon levels. Most importantly, this vaccine formulation led to ∼70% regression of established melanoma tumor. pH-sensitive liposomal vaccine administration elevated IgG2c/IgG1 antibody ratio, indicative of augmented OVA-specific Th1-biased immunity. Importantly, while the frequency of tumor-specific IFN-γ producing CD8+ T-cells was significantly increased, the M2-type anti-inflammatory macrophage levels were decreased in the tumor bed. In conclusion, our strategy induces reversal of immunosuppressive tumor microenvironment, while enhancing effective anti-tumor immune-response. We propose that this could be coupled with std. therapies during combating tumor eradication.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVCks7bE&md5=2eb22cda1e9a367c6e5e6757380a13ef
  58. 58
    Toy, R.; Keenum, M. C.; Pradhan, P.; Phang, K.; Chen, P.; Chukwu, C.; Nguyen, L. A. H.; Liu, J.; Jain, S.; Kozlowski, G.; Hosten, J.; Suthar, M. S.; Roy, K. TLR7 and RIG-I Dual-Adjuvant Loaded Nanoparticles Drive Broadened and Synergistic Responses in Dendritic Cells in Vitro and Generate Unique Cellular Immune Responses in Influenza Vaccination. J. Controlled Release 2021, 330, 866– 877,  DOI: 10.1016/j.jconrel.2020.10.060
    Google Scholar
    58
    TLR7 and RIG-I dual-adjuvant loaded nanoparticles drive broadened and synergistic responses in dendritic cells in vitro and generate unique cellular immune responses in influenza vaccination
    Toy, Randall; Keenum, M. Cole; Pradhan, Pallab; Phang, Katelynn; Chen, Patrick; Chukwu, Chinwendu; Nguyen, Lily Anh H.; Liu, Jiaying; Jain, Sambhav; Kozlowski, Gabrielle; Hosten, Justin; Suthar, Mehul S.; Roy, Krishnendu
    Journal of Controlled Release (2021), 330 (), 866-877CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    Although the existing flu vaccines elicit strong antigen-specific antibody responses, they fail to provide effective, long term protection - partly due to the absence of robust cellular memory immunity. We hypothesized that co-administration of combination adjuvants, mirroring the flu-virus related innate signaling pathways, could elicit strong cellular immunity. Here, we show that the small mol. adjuvant R848 and the RNA adjuvant PUUC, targeting endosomal TLR7s and cytoplasmic RLRs resp., when delivered together in polymer nanoparticles (NP), elicits a broadened immune responses in mouse bone marrow-derived dendritic cells (mBMDCs) and a synergistic response in both mouse and human plasmacytoid dendritic cells (pDCs). In mBMDCs, NP-R848-PUUC induced both NF-κB and interferon signaling. Interferon responses to co-delivered R848 and PUUC were additive in human peripheral blood mononuclear cells (PBMCs) and synergistic in human FLT3-differentiated mBMDCs and CAL-1 pDCs. Vaccination with NPs loaded with H1N1 Flu antigen, R848, and PUUC increased percentage of CD8+ T-cells in the lungs, percentage of antigen-specific CD4-T-cells in the spleen, and enhanced overall cytokine-secreting T cell percentages upon antigen restimulation. Also, in the spleen, T lymphopenia, esp. after in vitro restimulation with dual adjuvants, was obsd., indicating highly antigen-reactive T cells. Our results demonstrate that simultaneous engagement of TLR7 and RIG-I pathways using particulate carriers is a potential approach to improve cellular immunity in flu vaccination.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitlCku7rE&md5=4985b3db7e0bf52f50272a1d4e1238dc
  59. 59
    Hou, Y.; Wang, Y.; Tang, Y.; Zhou, Z.; Tan, L.; Gong, T.; Zhang, L.; Sun, X. Co-Delivery of Antigen and Dual Adjuvants by Aluminum Hydroxide Nanoparticles for Enhanced Immune Responses. J. Controlled Release 2020, 326, 120– 130,  DOI: 10.1016/j.jconrel.2020.06.021
    Google Scholar
    59
    Co-delivery of antigen and dual adjuvants by aluminum hydroxide nanoparticles for enhanced immune responses
    Hou, Yingying; Wang, Ying; Tang, Yao; Zhou, Zixuan; Tan, Lu; Gong, Tao; Zhang, Ling; Sun, Xun
    Journal of Controlled Release (2020), 326 (), 120-130CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    Adjuvants that contain pathogen-assocd. mol. patterns (PAMPs) can enhance vaccination efficacy by binding to pattern recognition receptors (PRRs), thereby stimulating immune responses. Particularly effective may be the combination of multiple PAMPs that activate different PRRs, which occurs with natural pathogens. Here we hypothesized the enhanced effects would occur in two adjuvants that stimulate different PRRs: CpG oligodeoxynucleotide (CpG-ODN), which is Toll-like receptor 9 agonist; and 5'-triphosphate, short, double-stranded RNA (3pRNA), which activates retinoic acid-inducible gene I (RIG-I). The model antigen ovalbumin (OVA) was loaded and adjuvants were surface-adsorbed to aluminum hydroxide nanoparticles (hereafter NP-3pRNA-CpG) by electrostatic interaction with an av. size of 120 nm and a neg. surface charge for targeting lymph nodes. These nanoparticles were efficiently internalized by antigen-presenting cells (APCs) in the lymph nodes, and the resulting APC activation and antigen cross-presentation generated strong humoral immunity and cytotoxic T lymphocyte responses and IFN-γ secretion. NP-3pRNA-CpG significantly suppressed B16-OVA tumor growth and prolonged survival of tumor-bearing mice in therapeutic and prophylactic models, illustrating the enhanced effects of CpG-ODN and 3pRNA. Our study highlights the potential of combining multiple adjuvants for effective vaccine design.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXht1Kgu7bL&md5=ec7771ba4a626526fd70d75d7fa0af14
  60. 60
    Pagendarm, H. M.; Stone, P. T.; Kimmel, B. R.; Baljon, J. J.; Aziz, M. H.; Pastora, L. E.; Hubert, L.; Roth, E. W.; Almunif, S.; Scott, E. A.; Wilson, J. T. Engineering Endosomolytic Nanocarriers of Diverse Morphologies Using Confined Impingement Jet Mixing. Nanoscale 2023, 15, 16016– 16029,  DOI: 10.1039/D3NR02874G
    Google Scholar
    60
    Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing
    Pagendarm, Hayden M.; Stone, Payton T.; Kimmel, Blaise R.; Baljon, Jessalyn J.; Aziz, Mina H.; Pastora, Lucinda E.; Hubert, Lauren; Roth, Eric W.; Almunif, Sultan; Scott, Evan A.; Wilson, John T.
    Nanoscale (2023), 15 (39), 16016-16029CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    The clin. translation of many biomol. therapeutics has been hindered by undesirable pharmacokinetic (PK) properties, inadequate membrane permeability, poor endosomal escape and cytosolic delivery, and/or susceptibility to degrdn. Overcoming these challenges merits the development of nanoscale drug carriers (nanocarriers) to improve the delivery of therapeutic cargo. Herein, we implement a flash nanopptn. (FNP) approach to produce nanocarriers of diverse vesicular morphologies by using various mol. wt. PEG-bl-DEAEMA-co-BMA (PEG-DB) polymers. We demonstrated that FNP can produce uniform (PDI < 0.1) particles after 5 impingements, and that by varying the copolymer hydrophilic mass fraction, FNP enables access to a diverse variety of nanoarchitectures including micelles, unilamellar vesicles (polymersomes), and multi-compartment vesicles (MCVs). We synthesized a library of 2 kDa PEG block copolymers, with DEAEMA-co-BMA second block mol. wts. of 3, 6, 12, 15, 20, and 30 kDa. All formulations were both pH responsive, endosomolytic, and capable of loading and cytosolically delivering small neg. charged mols. - albeit to different degrees. Using a B16. F10 melanoma model, we showcased the therapeutic potential of a lead FNP formulated PEG-DB nanocarrier, encapsulating the cyclic dinucleotide (CDN) cGAMP to activate the stimulator of interferon genes (STING) pathway in a therapeutically relevant context. Collectively, these data demonstrate that an FNP process can be used to formulate pH-responsive nanocarriers of diverse morphologies using a PEG-DB polymer system. As FNP is an industrially scalable process, these data address the crit. translational challenge of producing PEG-DB nanoparticles at scale. Furthermore, the diverse morphologies produced may specialize in the delivery of distinct biomol. cargos for other therapeutic applications, implicating the therapeutic potential of this platform in an array of disease applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhvF2qsLnK&md5=04a78b16072f0ff7e9436c3c62991260
  61. 61
    Manganiello, M. J.; Cheng, C.; Convertine, A. J.; Bryers, J. D.; Stayton, P. S. Diblock Copolymers with Tunable pH Transitions for Gene Delivery. Biomaterials 2012, 33, 2301– 2309,  DOI: 10.1016/j.biomaterials.2011.11.019
    Google Scholar
    61
    Diblock copolymers with tunable pH transitions for gene delivery
    Manganiello, Matthew J.; Cheng, Connie; Convertine, Anthony J.; Bryers, James D.; Stayton, Patrick S.
    Biomaterials (2012), 33 (7), 2301-2309CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
    A series of diblock copolymers contg. an endosomal-releasing segment composed of diethylaminoethyl methacrylate (DEAEMA) and Bu methacrylate (BMA) were synthesized via reversible addn.-fragmentation chain transfer (RAFT) polymn. The materials were designed to condense plasmid DNA (pDNA) through electrostatic interactions with a cationic poly(N,N-dimethylaminoethyl methacrylate) (DMAEMA) first block. The pDMAEMA was employed as a macro chain transfer agent (macroCTA) for the synthesis of a series in which the relative feed ratios of DEAEMA and BMA were systematically varied from 20% to 70% BMA. The resultant diblock copolymers exhibited low polydispersity (PDI ≤ 1.06) with similar mol. wts. (Mn = 19.3-23.1 kDa). Dynamic light scattering (DLS) measurements in combination with 1H NMR D2O studies demonstrated that the free copolymers assemble into core-shell micelles at physiol. pH. Redn. of the soln. pH to values representative of endosomal/lysosomal compartments induced an increase in the net cationic charge of the core through protonation of the DEAEMA residues. This protonation promotes micelle destabilization and exposure of the hydrophobic BMA residues that destabilize biol. membranes. The pH value at which this micelle-to-unimer transition occurred was dependent on the hydrophobic content of the copolymer, with higher BMA-contg. copolymer compns. exhibiting pH-induced transitions to the membrane-destabilizing state at successively lower pH values. The ability of the diblock copolymers to deliver pDNA was subsequently investigated using a GFP expression vector in two monocyte cell lines. High levels of DNA transfection were obsd. for the copolymer compns. exhibiting the sharpest pH transitions and membrane destabilizing activities, demonstrating the importance of tuning the endosomal-releasing segment compn.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xnt1entw%253D%253D&md5=ec63b85f138fe9934ba5508bf04e594f
  62. 62
    Allen, S.; Osorio, O.; Liu, Y. G.; Scott, E. Facile Assembly and Loading of Theranostic Polymersomes Via Multi-Impingement Flash Nanoprecipitation. J. Controlled Release 2017, 262, 91– 103,  DOI: 10.1016/j.jconrel.2017.07.026
    Google Scholar
    62
    Facile assembly and loading of theranostic polymersomes via multi-impingement flash nanoprecipitation
    Allen, Sean; Osorio, Omar; Liu, Yu-Gang; Scott, Evan
    Journal of Controlled Release (2017), 262 (), 91-103CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
    Flash nanopptn. has proven to be a powerful tool for the rapid and scalable assembly of solid-core nanoparticles from block copolymers. To date, FNP has not been applied for the fabrication of complex or vesicular nanoarchitectures capable of encapsulating hydrophilic mols. or bioactive protein therapeutics. Here, we present FNP as a single customizable method for the assembly of bicontinuous nanospheres, filomicelles and vesicular, multilamellar and tubular polymersomes from poly(ethylene glycol)-bl-poly(propylene sulfide) block copolymers. Multiple impingements of polymersomes assembled via FNP were shown to decrease vesicle diam. and polydispersity, allowing gram-scale fabrication of monodisperse polymersomes within minutes. Furthermore, we demonstrate that FNP supports simultaneous loading of both hydrophobic and hydrophilic mols. resp. into the polymersome membrane and aq. lumen, and encapsulated enzymes were found to be released and remain active following vesicle lysis. As an example application, theranostic polymersomes were generated via FNP that were dual loaded with the immunosuppressant rapamycin and a fluorescent dye to link targeted immune cells with the elicited immunomodulation of T cells. By expanding the capabilities of FNP, we present a rapid, scalable and reproducible method of nanofabrication for a wide range of nanoarchitectures that are typically challenging to assemble and load with therapeutics for controlled delivery and theranostic strategies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1egsbjK&md5=a52b3f1d74b3a23fe99693893e9eab06
  63. 63
    Han, J.; Zhu, Z.; Qian, H.; Wohl, A. R.; Beaman, C. J.; Hoye, T. R.; Macosko, C. W. A Simple Confined Impingement Jets Mixer for Flash Nanoprecipitation. J. Pharm. Sci. 2012, 101, 4018– 4023,  DOI: 10.1002/jps.23259
    Google Scholar
    63
    A simple confined impingement jets mixer for flash nanoprecipitation
    Han, Jing; Zhu, Zhengxi; Qian, Haitao; Wohl, Adam R.; Beaman, Charles J.; Hoye, Thomas R.; Macosko, Christopher W.
    Journal of Pharmaceutical Sciences (2012), 101 (10), 4018-4023CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
    Johnson and Prud'homme (2003. AICHE J 49:2264-2282) introduced the confined impingement jets (CIJ) mixer to prep. nanoparticles loaded with hydrophobic compds. (e.g., drugs, inks, fragrances, or pheromones) via flash nanopptn. (FNP). We have modified the original CIJ design to allow hand operation, eliminating the need for a syringe pump, and we added a second antisolvent diln. stage. Impingement mixing requires equal flow momentum from two opposing jets, one contg. the drug in org. solvent and the other contg. an antisolvent, typically water. The subsequent diln. step in the new design allows rapid quenching with high antisolvent concn. that enhances nanoparticle stability. This new CIJ with diln. (CIJ-D) mixer is a simple, cheap, and efficient device to produce nanoparticles. We have made 55 nm diam. β-carotene nanoparticles using the CIJ-D mixer. They are stable and reproducible in terms of particle size and distribution. We have also compared the performance of our CIJ-D mixer with the vortex mixer, which can operate at unequal flow rates (Liu et al., 2008. Chem Eng Sci 63:2829-2842), to make β-carotene-contg. particles over a series of turbulent conditions. On the basis of dynamic light scattering measurements, the new CIJ-D mixer produces stable particles of a size similar to the vortex mixer. Our CIJ-D design requires less vol. and provides an easily operated and inexpensive tool to produce nanoparticles via FNP and to evaluate new nanoparticle formulation. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVers70%253D&md5=c5e9605fc18c6dfbb6818cfe3a8888f6
  64. 64
    Johnson, B. K.; Prud’homme, R. K. Mechanism for Rapid Self-Assembly of Block Copolymer Nanoparticles. Phys. Rev. Lett. 2003, 91, 118302,  DOI: 10.1103/PhysRevLett.91.118302
    Google Scholar
    64
    Mechanism for Rapid Self-Assembly of Block Copolymer Nanoparticles
    Johnson, Brian K.; Prud'homme, Robert K.
    Physical Review Letters (2003), 91 (11), 118302/1-118302/4CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
    Amphiphilic block copolymers in soln. spontaneously self-assemble when the solvent quality for one block is selectively decreased. We demonstrate that, for supersatn. ratio changes [d(S)/dt] over 105 per s from equil., nanoparticles are obtained with a formation mechanism and size dependent on the jumping rate and magnitude. The threshold rate for homogeneous pptn. is detd. by the induction time of a particle, equiv. to the diffusion limited fusion of copolymer chains to form a corona of overlapping sol. brushes. Via detn. of the induction time with a novel confined impinging jets mixer and use of a scaling relation, the interfacial free energy of a block copolymer nanoparticle was measured for the first time.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1Oqurw%253D&md5=465c945d7870908649f6f231a6677a98
  65. 65
    Daniel, S.; Kis, Z.; Kontoravdi, C.; Shah, N. Quality by Design for Enabling RNA Platform Production Processes. Trends Biotechnol 2022, 40, 1213– 1228,  DOI: 10.1016/j.tibtech.2022.03.012
    Google Scholar
    65
    Quality by Design for enabling RNA platform production processes
    Daniel, Simon; Kis, Zoltan; Kontoravdi, Cleo; Shah, Nilay
    Trends in Biotechnology (2022), 40 (10), 1213-1228CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
    A review. RNA-based products have emerged as one of the most promising and strategic technologies for global vaccination, infectious disease control, and future therapy development. The assessment of crit. quality attributes (CQAs), product-process interactions, relevant process anal. technologies, and process modeling capabilities can feed into a robust Quality by Design (QbD) framework for future development, design, and control of manufg. processes. QbD implementation will help the RNA technol. reach its full potential and will be central to the development, pre-qualification, and regulatory approval of rapid response, disease-agnostic RNA platform prodn. processes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpvVahurs%253D&md5=7b64c147111978920111452f652888dc
  66. 66
    Warne, N.; Ruesch, M.; Siwik, P.; Mensah, P.; Ludwig, J.; Hripcsak, M.; Godavarti, R.; Prigodich, A.; Dolsten, M. Delivering 3 Billion Doses of Comirnaty in 2021. Nat. Biotechnol. 2023, 41, 183– 188,  DOI: 10.1038/s41587-022-01643-1
    Google Scholar
    66
    Delivering 3 billion doses of Comirnaty in 2021
    Warne, Nicholas; Ruesch, Margaret; Siwik, Pamela; Mensah, Paul; Ludwig, John; Hripcsak, Michael; Godavarti, Ranga; Prigodich, Andrew; Dolsten, Mikael
    Nature Biotechnology (2023), 41 (2), 183-188CODEN: NABIF9; ISSN:1087-0156. (Nature Portfolio)
    Pfizer created a 'light-speed' approach to meet the challenge of vaccinating the world against COVID-19. It involved developing new strategies for all aspects of vaccine development, from sourcing materials and scaling up manufg. to transportation and dosing.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXis1Sjs7o%253D&md5=c0125b7d1eb92de3d174e35c99a37aec
  67. 67
    Chang, T. Z.; Stadmiller, S. S.; Staskevicius, E.; Champion, J. A. Effects of Ovalbumin Protein Nanoparticle Vaccine Size and Coating on Dendritic Cell Processing. Biomater Sci. 2017, 5, 223– 233,  DOI: 10.1039/C6BM00500D
    Google Scholar
    67
    Effects of ovalbumin protein nanoparticle vaccine size and coating on dendritic cell processing
    Chang, Timothy Z.; Stadmiller, Samantha S.; Staskevicius, Erika; Champion, Julie A.
    Biomaterials Science (2017), 5 (2), 223-233CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)
    Nanoparticle vaccine delivery platforms are a promising technol. for enhancing vaccine immunogenicity. Protein nanoparticles (PNPs), made entirely from antigen, have been shown to induce protective immune responses against influenza. However, the fundamental mechanisms by which PNPs enhance component protein immunogenicity are not understood. Here, we investigate the role of size and coating of model ovalbumin (OVA) PNPs on particle uptake and trafficking, as well as on inflammation and maturation factor expression in dendritic cells (DCs) in vitro. OVA PNPs enhance antigen uptake in a size-independent manner, and experience attenuated endosomal acidification as compared to sol. OVA. OVA PNPs also trigger Fc receptor upregulation. Expression of cytokines IL-1β and TNF-α were PNP size- and coating-dependent, with small (∼270 nm) nanoparticles triggering greater inflammatory cytokine prodn. than large (∼560 nm) particles. IL-1β expression by DCs in response to PNP stimulation implies activation of the inflammasome, a pathway known to be activated by certain types of nanoparticulate adjuvants. The attenuated acidification and pro-inflammatory profile generated by PNPs in DCs demonstrate that phys. biomaterial properties can modulate dendritic cell-mediated antigen processing and adjuvancy. In addn. to nanoparticles' enhancement of DC antigen uptake, our work suggests that vaccine nanoparticle size and coating are uptake-independent modulators of immunogenicity.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvF2gurnK&md5=2847bc4357609887cd5580a2ae9eef75
  68. 68
    Thomas, S. N.; Schudel, A. Overcoming Transport Barriers for Interstitial-, Lymphatic-, and Lymph Node-Targeted Drug Delivery. Curr. Opin Chem. Eng. 2015, 7, 65– 74,  DOI: 10.1016/j.coche.2014.11.003
    Google Scholar
    68
    Overcoming transport barriers for interstitial-, lymphatic-, and lymph node-targeted drug delivery
    Thomas Susan N; Schudel Alex
    Current opinion in chemical engineering (2015), 7 (), 65-74 ISSN:2211-3398.
    Despite drug formulation improving circulation times and targeting, efficacy is stymied by inadequate penetration into and retention within target tissues. This review highlights the barriers restricting delivery to the connective tissue interstitium, lymphatics, and lymph nodes as well as advances in engineering drug carriers to overcome these delivery challenges. Three-dimensional tissue physiology is discussed in the context of providing material design principles for delivery to these tissues; in particular the influence of interstitial and lymphatic flows as well as differential permeabilities of the blood and lymphatic capillaries. Key examples of materials with different characteristics developed to overcome these transport barriers are discussed as well as potential areas for further development.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srotF2rsQ%253D%253D&md5=3253ad4ef935260a93f650e74b980196
  69. 69
    Munson, M. J.; O’Driscoll, G.; Silva, A. M.; Lazaro-Ibanez, E.; Gallud, A.; Wilson, J. T.; Collen, A.; Esbjorner, E. K.; Sabirsh, A. A High-Throughput Galectin-9 Imaging Assay for Quantifying Nanoparticle Uptake, Endosomal Escape and Functional RNA Delivery. Commun. Biol. 2021, 4, 211,  DOI: 10.1038/s42003-021-01728-8
    Google Scholar
    69
    A high-throughput Galectin-9 imaging assay for quantifying nanoparticle uptake, endosomal escape and functional RNA delivery
    Munson, Michael J.; O'Driscoll, Gwen; Silva, Andreia M.; Lazaro-Ibanez, Elisa; Gallud, Audrey; Wilson, John T.; Collen, Anna; Esbjoerner, Elin K.; Sabirsh, Alan
    Communications Biology (2021), 4 (1), 211CODEN: CBOIDQ; ISSN:2399-3642. (Nature Research)
    RNA-based therapies have great potential to treat many undruggable human diseases. However, their efficacy, in particular for mRNA, remains hampered by poor cellular delivery and limited endosomal escape. Development and optimization of delivery vectors, such as lipid nanoparticles (LNPs), are impeded by limited screening methods to probe the intracellular processing of LNPs in sufficient detail. We have developed a high-throughput imaging-based endosomal escape assay utilizing a Galectin-9 reporter and fluorescently labeled mRNA to probe correlations between nanoparticle-mediated uptake, endosomal escape frequency, and mRNA translation. Furthermore, this assay has been integrated within a screening platform for optimization of lipid nanoparticle formulations. We show that Galectin-9 recruitment is a robust, quant. reporter of endosomal escape events induced by different mRNA delivery nanoparticles and small mols. We identify nanoparticles with superior escape properties and demonstrate cell line variances in endosomal escape response, highlighting the need for fine-tuning of delivery formulations for specific applications.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtV2iurvI&md5=2f6c6521ab150ffdcc94a614266cd245
  70. 70
    Shae, D.; Becker, K. W.; Christov, P.; Yun, D. S.; Lytton-Jean, A. K. R.; Sevimli, S.; Ascano, M.; Kelley, M.; Johnson, D. B.; Balko, J. M.; Wilson, J. T. Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy. Nat. Nanotechnol 2019, 14, 269– 278,  DOI: 10.1038/s41565-018-0342-5
    Google Scholar
    70
    Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy
    Shae, Daniel; Becker, Kyle W.; Christov, Plamen; Yun, Dong Soo; Lytton-Jean, Abigail K. R.; Sevimli, Sema; Ascano, Manuel; Kelley, Mark; Johnson, Douglas B.; Balko, Justin M.; Wilson, John T.
    Nature Nanotechnology (2019), 14 (3), 269-278CODEN: NNAABX; ISSN:1748-3387. (Nature Research)
    Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutics that activate innate immunity to increase tumor immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance and inefficient transport to the cytosol where STING is localized. Here, we describe STING-activating nanoparticles (STING-NPs)-rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2'3' cGMP-adenosine monophosphate (cGAMP). STING-NPs increase the biol. potency of cGAMP, enhance STING signaling in the tumor microenvironment and sentinel lymph node, and convert immunosuppressive tumors to immunogenic, tumoricidal microenvironments. This leads to enhanced therapeutic efficacy of cGAMP, inhibition of tumor growth, increased rates of long-term survival, improved response to immune checkpoint blockade and induction of immunol. memory that protects against tumor rechallenge. We validate STING-NPs in freshly isolated human melanoma tissue, highlighting their potential to improve clin. outcomes of immunotherapy.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtVGitbo%253D&md5=4b95f1d3ac44492fd975fc9e37bcec58
  71. 71
    Zheng, S.; Wang, W.; Aldahdooh, J.; Malyutina, A.; Shadbahr, T.; Tanoli, Z.; Pessia, A.; Tang, J. Synergyfinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets. Genomics Proteomics Bioinformatics 2022, 20, 587– 596,  DOI: 10.1016/j.gpb.2022.01.004
    Google Scholar
    71
    SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets
    Zheng Shuyu; Wang Wenyu; Aldahdooh Jehad; Malyutina Alina; Shadbahr Tolou; Tanoli Ziaurrehman; Pessia Alberto; Tang Jing
    Genomics, proteomics & bioinformatics (2022), 20 (3), 587-596 ISSN:.
    Combinatorial therapies have been recently proposed to improve the efficacy of anticancer treatment. The SynergyFinder R package is a software used to analyze pre-clinical drug combination datasets. Here, we report the major updates to the SynergyFinder R package for improved interpretation and annotation of drug combination screening results. Unlike the existing implementations, the updated SynergyFinder R package includes five main innovations. 1) We extend the mathematical models to higher-order drug combination data analysis and implement dimension reduction techniques for visualizing the synergy landscape. 2) We provide a statistical analysis of drug combination synergy and sensitivity with confidence intervals and P values. 3) We incorporate a synergy barometer to harmonize multiple synergy scoring methods to provide a consensus metric for synergy. 4) We evaluate drug combination synergy and sensitivity to provide an unbiased interpretation of the clinical potential. 5) We enable fast annotation of drugs and cell lines, including their chemical and target information. These annotations will improve the interpretation of the mechanisms of action of drug combinations. To facilitate the use of the R package within the drug discovery community, we also provide a web server at www.synergyfinderplus.org as a user-friendly interface to enable a more flexible and versatile analysis of drug combination data.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB2M7jslymtA%253D%253D&md5=586c7516cf1d71a67d4788d4e640754e
  72. 72
    Mouries, J.; Moron, G.; Schlecht, G.; Escriou, N.; Dadaglio, G.; Leclerc, C. Plasmacytoid Dendritic Cells Efficiently Cross-Prime Naive T Cells in Vivo after TLR Activation. Blood 2008, 112, 3713– 3722,  DOI: 10.1182/blood-2008-03-146290
    Google Scholar
    72
    Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation
    Mouries, Juliette; Moron, Gabriel; Schlecht, Geraldine; Escriou, Nicolas; Dadaglio, Gilles; Leclerc, Claude
    Blood (2008), 112 (9), 3713-3722CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)
    Cross-presentation is a crucial mechanism in tumoral and microbial immunity because it allows internalized cell assocd. or exogenous antigens (Ags) to be delivered into the major histocompatibility complex I pathway. This pathway is important for the development of CD8+ T-cell responses and for the induction of tolerance. In mice, cross-presentation is considered to be a unique property of CD8α+ conventional dendritic cells (DCs). Here we show that splenic plasmacytoid DCs (pDCs) efficiently capture exogenous Ags in vivo but are not able to cross-present these Ags at steady state. However, in vitro and in vivo stimulation by Toll-like receptor-7, or -9 or viruses licenses pDCs to cross-present sol. or particulate Ags by a transporter assocd. with antigen processing-dependent mechanism. Induction of cross-presentation confers to pDCs the ability to generate efficient effector CD8+ T-cell responses against exogenous Ags in vivo, showing that pDCs may play a crucial role in induction of adaptive immune responses against pathogens that do not infect tissues of hemopoietic origin. This study provides the first evidence for an in vivo role of splenic pDCs in Ag cross-presentation and T-cell cross-priming and suggests that pDCs may constitute an attractive target to boost the efficacy of vaccines based on cytotoxic T lymphocyte induction.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlCntrvF&md5=6484bd424f61a2bcf69ee7076b403ea6
  73. 73
    Villadangos, J. A.; Young, L. Antigen-Presentation Properties of Plasmacytoid Dendritic Cells. Immunity 2008, 29, 352– 361,  DOI: 10.1016/j.immuni.2008.09.002
    Google Scholar
    73
    Antigen-presentation properties of plasmacytoid dendritic cells
    Villadangos, Jose A.; Young, Louise
    Immunity (2008), 29 (3), 352-361CODEN: IUNIEH; ISSN:1074-7613. (Cell Press)
    A review. One of the remaining enigmas of the dendritic cell (DC) network is the potential contribution of plasmacytoid DCs (pDCs) to antigen presentation. Although the antigen-presentation capacity of conventional DCs (cDCs) is clearly defined, pDCs are generally attributed as having little, if any, antigen-presentation function. Instead, pDCs are regarded as immunomodulating cells, capable of directing the immune response through their secretion of large amts. of type I interferons. Here, the authors examine the evidence for a potential role of pDC in antigen capture, processing, and presentation to T cells at sites of infection and in the lymph nodes.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtF2jtLvL&md5=81e1c944723cfa0bc4117416b558dad0
  74. 74
    Hildner, K.; Edelson, B. T.; Purtha, W. E.; Diamond, M.; Matsushita, H.; Kohyama, M.; Calderon, B.; Schraml, B. U.; Unanue, E. R.; Diamond, M. S.; Schreiber, R. D.; Murphy, T. L.; Murphy, K. M. Batf3 Deficiency Reveals a Critical Role for CD8α+ Dendritic Cells in Cytotoxic T Cell Immunity. Science 2008, 322, 1097– 1100,  DOI: 10.1126/science.1164206
    Google Scholar
    74
    Batf3 Deficiency Reveals a Critical Role for CD8α+ Dendritic Cells in Cytotoxic T Cell Immunity
    Hildner, Kai; Edelson, Brian T.; Purtha, Whitney E.; Diamond, Mark; Matsushita, Hirokazu; Kohyama, Masako; Calderon, Boris; Schraml, Barbara U.; Unanue, Emil R.; Diamond, Michael S.; Schreiber, Robert D.; Murphy, Theresa L.; Murphy, Kenneth M.
    Science (Washington, DC, United States) (2008), 322 (5904), 1097-1100CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8α+ dendritic cells, in vivo anal. has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8α+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3-/- mice were defective in cross-presentation, and Batf3-/- mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice. These results suggest an important role for CD8α+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlGhu7fF&md5=5edf74e0adedb0e092d59a241a711784
  75. 75
    Kaech, S. M.; Wherry, E. J.; Ahmed, R. Effector and Memory T-Cell Differentiation: Implications for Vaccine Development. Nat. Rev. Immunol 2002, 2, 251– 262,  DOI: 10.1038/nri778
    Google Scholar
    75
    Effector and memory T-cell differentiation: implications for vaccine development
    Kaech, Susan M.; Wherry, E. John; Ahmed, Rafi
    Nature Reviews Immunology (2002), 2 (4), 251-262CODEN: NRIABX; ISSN:1474-1733. (Nature Publishing Group)
    A review. Recent work shows that after stimulation with antigen, CD4+ and CD8+ T cells embark on a program of proliferation that is closely linked with the acquisition of effector functions and leads ultimately to memory-cell formation. Here, we discuss the signals required for commitment to this program of development and the factors that might influence its progression. Models of the pathways of effector and memory T-cell differentiation are discussed, and we highlight the implications of this new understanding for the optimization of vaccine strategies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFKhtrc%253D&md5=7a63c84ffcfeae8b4362befd059980e3
  76. 76
    Taylor, M. A.; Hughes, A. M.; Walton, J.; Coenen-Stass, A. M. L.; Magiera, L.; Mooney, L.; Bell, S.; Staniszewska, A. D.; Sandin, L. C.; Barry, S. T. Longitudinal Immune Characterization of Syngeneic Tumor Models to Enable Model Selection for Immune Oncology Drug Discovery. J. Immunother Cancer 2019, 7, 328,  DOI: 10.1186/s40425-019-0794-7
    Google Scholar
    76
    Longitudinal immune characterization of syngeneic tumor models to enable model selection for immune oncology drug discovery
    Taylor Molly A; Hughes Adina M; Walton Josephine; Coenen-Stass Anna M L; Magiera Lukasz; Mooney Lorraine; Bell Sigourney; Staniszewska Anna D; Sandin Linda C; Barry Simon T; Watkins Amanda; Carnevalli Larissa S; Hardaker Elizabeth L; Mooney Lorraine
    Journal for immunotherapy of cancer (2019), 7 (1), 328 ISSN:.
    BACKGROUND: The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as αPD-1, αPD-L1, and αCTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. METHODS: Using flow cytometry, O-link protein analysis, RT-PCR, and RNAseq we have characterized kinetic changes in immune-cell populations over the course of tumor development in commonly used syngeneic models. RESULTS: This longitudinal profiling of syngeneic models enables pharmacodynamic time point selection within each model, dependent on the immune population of interest. Additionally, we have characterized the changes in immune populations in each of these models after treatment with the combination of α-PD-L1 and α-CTLA-4 antibodies, enabling benchmarking to known immune modulating treatments within each model. CONCLUSIONS: Taken together, this dataset will provide a framework for characterization and enable the selection of the optimal models for immunotherapy combinations and generate potential biomarkers for clinical evaluation in identifying responders and non-responders to immunotherapy combinations.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MfksVSntA%253D%253D&md5=7b3308ccad3e1cbb161737db47069240
  77. 77
    Wang-Bishop, L.; Wehbe, M.; Shae, D.; James, J.; Hacker, B. C.; Garland, K.; Chistov, P. P.; Rafat, M.; Balko, J. M.; Wilson, J. T. Potent Sting Activation Stimulates Immunogenic Cell Death to Enhance Antitumor Immunity in Neuroblastoma. J. Immunother Cancer 2020, 8, e000282,  DOI: 10.1136/jitc-2019-000282
    Google Scholar
    There is no corresponding record for this reference.
  78. 78
    Kilchrist, K. V.; Dimobi, S. C.; Jackson, M. A.; Evans, B. C.; Werfel, T. A.; Dailing, E. A.; Bedingfield, S. K.; Kelly, I. B.; Duvall, C. L. Gal8 Visualization of Endosome Disruption Predicts Carrier-Mediated Biologic Drug Intracellular Bioavailability. ACS Nano 2019, 13, 1136– 1152,  DOI: 10.1021/acsnano.8b05482
    Google Scholar
    78
    Gal8 Visualization of Endosome Disruption Predicts Carrier-Mediated Biologic Drug Intracellular Bioavailability
    Kilchrist, Kameron V.; Dimobi, Somtochukwu C.; Jackson, Meredith A.; Evans, Brian C.; Werfel, Thomas A.; Dailing, Eric A.; Bedingfield, Sean K.; Kelly, Isom B.; Duvall, Craig L.
    ACS Nano (2019), 13 (2), 1136-1152CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Endolysosome entrapment is one of the key barriers to the therapeutic use of biol. drugs that act intracellularly. The screening of prospective nanoscale endosome-disrupting delivery technologies is currently limited by methods that are indirect and cumbersome. Here, we statistically validate Galectin 8 (Gal8) intracellular tracking as a superior approach that is direct, quant., and predictive of therapeutic cargo intracellular bioactivity through in vitro high-throughput screening and in vivo validation. Gal8 is a cytosolically dispersed protein that, when endosomes are disrupted, redistributes by binding to glycosylation moieties selectively located on the inner face of endosomal membranes. The quant. redistribution of a Gal8 fluorescent fusion protein from the cytosol into endosomes is demonstrated as a real-time, live-cell assessment of endosomal integrity that does not require labeling or modification of either the carrier or the biol. drug and that allows quant. distinction between closely related, endosome-disruptive drug carriers. Through screening two families of siRNA polymeric carrier compns. at varying dosages, we show that Gal8 endosomal recruitment correlates strongly (r = 0.95 and p < 10-4) with intracellular siRNA bioactivity. Through this screen, we gathered insights into how compn. and mol. wt. affect endosome disruption activity of poly[(ethylene glycol)-b-[(2-(dimethylamino)ethyl methacrylate)-co-(Bu methacrylate)]] [PEG-(DMAEMA-co-BMA)] siRNA delivery systems. Addnl. studies showed that Gal8 recruitment predicts intracellular bioactivity better than current std. methods such as Lysotracker colocalization (r = 0.35, not significant), pH-dependent hemolysis (not significant), or cellular uptake (r = 0.73 and p < 10-3). Importantly, the Gal8 recruitment method is also amenable to fully objective high-throughput screening using automated image acquisition and quant. image anal., with a robust estd. Z' of 0.6 (whereas assays with Z' > 0 have high-throughput screening utility). Finally, we also provide measurements of in vivo endosomal disruption based on Gal8 visualization (p < 0.03) of a nanocarrier formulation confirmed to produce significant cytosolic delivery and bioactivity of siRNA within tumors (p < 0.02). In sum, this report establishes the utility of Gal8 subcellular tracking for the rapid optimization and high-throughput screening of the endosome disruption potency of intracellular delivery technologies.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht12qs7w%253D&md5=35d2d7494c1933249faf76094de990cf

Cited By

Click to copy section linkSection link copied!

This article is cited by 1 publications.

  1. Dehua Lu, Wenhua Li, Jingyun Tan, Ying Li, Wei Mao, Yuanyuan Zheng, Muwen Yang, Jin Wang, Weihu Wang, Shubin Wang, Jing Gao, Yajie Liu. STING Agonist Delivered by Neutrophil Membrane-Coated Gold Nanoparticles Exerts Synergistic Tumor Inhibition with Radiotherapy. ACS Applied Materials & Interfaces 2024, 16 (40) , 53474-53488. https://doi.org/10.1021/acsami.4c09825
Download PDF
Go to ACS Nano
Get e-Alerts
Get e-Alerts

ACS Nano

Cite this: ACS Nano 2024, 18, 9, 6845–6862
Click to copy citationCitation copied!
https://doi.org/10.1021/acsnano.3c04471
Published February 22, 2024

Copyright © 2024 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Article Views

6013

Altmetric

-

Citations

1
Learn about these metrics

Article Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.

Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.

The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.

  • Abstract

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 1

    Figure 1. Fabrication and characterization of nanoparticle platform. (A) Schematic representation of coloaded nanoparticle vaccine platform promoting MPLA delivery to cell surface and endosome, and cGAMP and peptide antigen delivery to cytosol via endosomal escape. This enhances innate immune signaling for dendritic cell activation and antigen presentation on MHC-I, which together activate a CD8+ T cell response. Made with BioRender.com. (B) Chemical composition and structure of mPEG-block-(DEAEMA-co-BMA) diblock copolymer. (C) Schematic representation of formulation of nanoparticle via confined impingement jet mixing. Made with BioRender.com. (D) Representative cryogenic electron micrograph of nanoparticle coloaded with antigen, cGAMP, and MPLA. (E) Representative size distribution of empty nanoparticle and nanoparticle coloaded with antigen, cGAMP, and MPLA as measured by dynamic light scattering. (F) Representative fluorescent images of NCI H358 cells expressing a Gal9-mCherry fusion protein after treatment with PBS or the loaded nanoparticle (NP). (G) Vesicle count per cell for NCI H358 cells expressing a Gal9-mCherry fusion protein after treatment with indicated formulations (mean ± SD; n = 3–11 biologically independent samples, **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (H) In vitro evaluation of IRF3 and NF-κB activation after treatment with indicated formulation for 24 h (mean ± SD; n = 3 biologically independent samples).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 2

    Figure 2. Combining NP-cGAMP and NP-MPLA enhances innate immune activation, co-stimulatory molecule expression, and pro-inflammatory cytokine secretion in vitro. (A) In vitro evaluation of interferon activation in RAW-Dual reporter cells after treatment with indicated formulation for 24 h, cGAMP doses indicated on x-axis, MPLA dose for NP-MPLA dose matched to MPLA dose in cGAMP:MPLA 1:16 (mean ± SD; n = 3 biologically independent samples). (B) In vitro evaluation of NF-κB activation in RAW-Dual reporter cells after treatment with indicated formulation for 24 h, MPLA doses indicated on x-axis, cGAMP dose for NP-cGAMP dose matched to cGAMP dose in cGAMP:MPLA 16:1 (mean ± SD; n = 3 biologically independent samples). (C) Flow cytometric quantification of mean fluorescence intensity (MFI) of CD86 expression by BMDCs treated with indicated doses of NP-cGAMP, NP-MPLA, or a mixture of both NPs (n = 3 biologically independent samples). (D–G) Concentration of secreted IFN-β (D), IL-6 (E), TNF-α (F), and IL-1α (G) by BMDCs after treatment with indicated doses of NP-cGAMP, NP-MPLA, or a mixture of both NPs (n = 3 biologically independent samples).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 3

    Figure 3. NP-cGAMP/MPLA enhances innate immune activation, co-stimulatory molecule expression, and pro-inflammatory cytokine secretion in vitro. (A) In vitro evaluation of interferon activation in RAW-Dual reporter cells after treatment with indicated formulation for 24 h, cGAMP doses indicated on x-axis, MPLA dose for NP-MPLA dose matched to MPLA dose in NP-cGAMP/MPLA(1:4) (mean ± SD; n = 3 biologically independent samples). (B) In vitro evaluation of NF-κB activation in RAW-Dual reporter cells after treatment with indicated formulation for 24 h, MPLA doses indicated on x-axis, cGAMP dose for NP-cGAMP dose matched to cGAMP dose in NP-cGAMP/MPLA(4:1) (mean ± SD; n = 3 biologically independent samples). (C) Flow cytometric quantification of mean fluorescence intensity (MFI) of CD86 expression by BMDCs treated with indicated doses of NP-cGAMP, NP-MPLA, or NP-cGAMP/MPLA (n = 3 biologically independent samples). (D–G) Concentration of secreted (D) IFN-β, (E) IL-6, (F) TNF-α, and (G) IL-1α by BMDCs after treatment with indicated doses of NP-cGAMP, NP-MPLA, or NP-cGAMP/MPLA (n = 3 biologically independent samples).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 4

    Figure 4. Nanoparticle vaccine enhances lymphatic accumulation and uptake by antigen presenting cells. (A) Fluorescent images of vaccine site draining lymph node 6h after subcutaneous injection of vaccine formulated with Cy5-OVAp. (B) Quantification of fluorescence in vaccine site draining lymph node (mean ± SD; n = 5 mice/group; **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (C) Percentage of Cy5-OVAp positive cells among immune cell populations in vaccine draining lymph node 6h after injection of vaccine formulated with Cy5-OVAp (mean ± SD; n = 5 mice/group; ***P < 0.001; one-way ANOVA with Tukey’s multiple comparisons). (D) Percentage of Cy5-OVAp positive cells among pDCs and cDCs (cDC1 and cDC2) in the vaccine site draining lymph node 6h after injection of vaccine formulated with Cy5-OVAp (mean ± SD; n = 6–8 mice/group; *P < 0.05, **P < 0.01; unpaired t test).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 5

    Figure 5. Nanoparticle vaccine enhances dendritic cell activation and cross-presentation, activates antigen-specific CD8+ T cells, and provides therapeutic efficacy in the EG7.OVA model. (A) Flow cytometric quantification of mean fluorescence intensity (MFI) of CD86 expression by BMDCs treated with indicated formulations (mean ± SD; n = 2; **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (B) Flow cytometric quantification of mean fluorescence intensity (MFI) or percentage of SIINFEKL-H2Kb positive BMDCs treated with indicated formulations and stained with PE-labeled antibody against SIINFEKL/H-2Kb (mean ± SD; n = 3; ****P < 0.0001; one-way ANOVA with Tukey’s multiple comparisons). (C) Vaccination and downstream analysis scheme. (D) Quantification of the frequency of SIINFEKL-specific CD8+ T cells in spleen after vaccination using peptide/MHC tetramer staining (mean ± SD; n = 10 mice/group; ****P < 0.0001; one-way ANOVA with Tukey’s multiple comparisons). (E) Quantification of the frequency of SIINFEKL-specific CD8+ T cells in spleen after vaccination using peptide/MHC tetramer staining comparing wild-type mice to Batf3–/– mice (mean ± SD; n = 5–8 mice/group; ***P < 0.001, ****P < 0.0001; two-way ANOVA with Tukey’s multiple comparisons). (F) Tumor challenge and therapeutic vaccination scheme. (G) Average EG7.OVA tumor growth in response to indicated formulation (mean ± SEM; n = 8–10 mice/group). (H) Average tumor volume on day 20 after tumor inoculation (mean ± SEM; n = 8–10 mice/group; **P < 0.01, ***P < 0.001; one-way ANOVA with Tukey’s multiple comparisons). (I) Kaplan–Meier survival curve using 2000 mm3 tumor volume as the end point (n = 8–10 mice/group; statistical significance between indicated treatment versus PBS and NP-Pep/cGAMP; *P < 0.05, **P < 0.01; Mantel–Cox log-rank test). (J) Representative flow cytometry plots and quantification of IFNγ+TNFα+ CD8+ T cells after ex vivo restimulation of splenocytes with SIINFEKL peptide (mean ± SD; n = 8 mice/group; ****P < 0.0001; unpaired t test). (K) Percentage of central and effector memory antigen-specific CD8+ T cells (TCM and TEM) in spleen after vaccination (mean ± SD; n = 8 mice/group; ****P < 0.0001; unpaired t test).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 6

    Figure 6. Nanoparticle vaccine provides therapeutic efficacy in MC38 adenocarcinoma model and improves the efficacy of αPD-1 ICB therapy. (A) Tumor challenge and therapeutic vaccination scheme. (B) Spider plots of individual tumor growth curves. (C) Average MC38 tumor growth in response to indicated formulation (mean ± SEM; n = 10 mice/group). (D) Average tumor volume on day 22 after tumor inoculation (mean ± SEM; n = 10 mice/group; *P < 0.05; one-way ANOVA with Tukey’s multiple comparisons). (E) Kaplan–Meier survival curve using 2000 mm3 tumor volume as the end point (n = 10 mice/group; statistical significance between NP-Pep/cGAMP/MPLA(1:4) and all other groups shown; *P < 0.05; Mantel–Cox log-rank test). (F) Tumor challenge, therapeutic vaccination, and αPD-1 treatment scheme. (G) Spider plots of individual tumor growth curves. (H) Average MC38 tumor growth in response to indicated formulation (mean ± SEM; n = 8–10 mice/group). (I) Average tumor volume on days 17–25 after tumor inoculation (mean ± SEM; n = 8–10 mice/group; *P < 0.05, **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (J) Kaplan–Meier survival curve using 2000 mm3 tumor volume as the end point (n = 8–10 mice/group; statistical significance between NP-Pep/cGAMP/MPLA(1:4) + αPD-1 and all other groups shown; *P < 0.05; Mantel–Cox log-rank test).

    High Resolution Image
    Download MS PowerPoint Slide

    Figure 7

    Figure 7. Nanoparticle vaccine activates antigen-specific and functional CD8+ T cells against MC38 neoantigens. (A) Vaccination and downstream analysis scheme. (B) Quantification of the frequency of Reps1-specific and Adpgk-specific CD8+ T cells in spleen after vaccination using peptide/MHC tetramer staining (mean ± SD; n = 7–8 mice/group; *P < 0.05, **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (C) Percentage of central and effector memory antigen-specific CD8+ T cells in spleen after vaccination (mean ± SD; n = 7–8 mice/group; ****P < 0.0001; two-way ANOVA with Tukey’s multiple comparisons). (D) Representative ICCS flow cytometry plots evaluating the percentage of IFNγ+TNFα+ CD8+ T cells after ex vivo restimulation of splenocytes with Reps1 (AQLANDVVL) or Adpgk (ASMTNMELM) peptides. (E) Quantification of flow cytometry data in D (mean ± SD; n = 7–8 mice/group; *P < 0.05, **P < 0.01; one-way ANOVA with Tukey’s multiple comparisons). (F) Representative ELISPOT wells after ex vivo restimulation of splenocytes with Reps1 (AQLANDVVL) or Adpgk (ASMTNMELM) peptides. (G) Quantification of images in F to determine the CD8+IFNγ+ T cell response (mean ± SD; n = 7–8 mice/group; *P < 0.05, **P < 0.01, ****P < 0.0001; one-way ANOVA with Tukey’s multiple comparisons).

    High Resolution Image
    Download MS PowerPoint Slide

  • References

    This article references 78 other publications.

    1. 1
      Korman, A. J.; Garrett-Thomson, S. C.; Lonberg, N. The Foundations of Immune Checkpoint Blockade and the Ipilimumab Approval Decennial. Nat. Rev. Drug Discov 2022, 21, 509– 528,  DOI: 10.1038/s41573-021-00345-8
      1
      The foundations of immune checkpoint blockade and the ipilimumab approval decennial
      Korman, Alan J.; Garrett-Thomson, Sarah C.; Lonberg, Nils
      Nature Reviews Drug Discovery (2022), 21 (7), 509-528CODEN: NRDDAG; ISSN:1474-1776. (Nature Portfolio)
      Cancer immunity, and the potential for cancer immunotherapy, have been topics of scientific discussion and experimentation for over a hundred years. Several successful cancer immunotherapies - such as IL-2 and interferon-a (IFNa) - have appeared over the past 30 years. However, it is only in the past decade that immunotherapy has made a broad impact on patient survival in multiple high-incidence cancer indications. The emergence of immunotherapy as a new pillar of cancer treatment (adding to surgery, radiation, chemotherapy and targeted therapies) is due to the success of immune checkpoint blockade (ICB) drugs, the first of which - ipilimumab - was approved in 2011. ICB drugs block receptors and ligands involved in pathways that attenuate T cell activation - such as cytotoxic T lymphocyte antigen 4 (CTLA4), programed cell death 1 (PD1) and its ligand, PDL1 - and prevent, or reverse, acquired peripheral tolerance to tumor antigens. In this Review we mark the tenth anniversary of the approval of ipilimumab and discuss the foundational scientific history of ICB, together with the history of the discovery, development and elucidation of the mechanism of action of the first generation of drugs targeting the CTLA4 and PD1 pathways.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXivValtr%252FJ&md5=4d70b7f025350759038f63b701a6c494
    2. 2
      Sharma, P.; Allison, J. P. The Future of Immune Checkpoint Therapy. Science 2015, 348, 56– 61,  DOI: 10.1126/science.aaa8172
      2
      The future of immune checkpoint therapy
      Sharma, Padmanee; Allison, James P.
      Science (Washington, DC, United States) (2015), 348 (6230), 56-61CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      A review. Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clin. advances and provided a new weapon against cancer. This therapy has elicited durable clin. responses and, in a fraction of patients, long-term remissions where patients exhibit no clin. signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of addnl. pathways that will need to be targeted through combination therapies to provide survival benefit for greater nos. of patients.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXls1Wmurg%253D&md5=d63ae85b9c651ec64a3b5b002c609e35
    3. 3
      Shum, B.; Larkin, J.; Turajlic, S. Predictive Biomarkers for Response to Immune Checkpoint Inhibition. Semin Cancer Biol. 2022, 79, 4– 17,  DOI: 10.1016/j.semcancer.2021.03.036
      3
      Predictive biomarkers for response to immune checkpoint inhibition
      Shum, Benjamin; Larkin, James; Turajlic, Samra
      Seminars in Cancer Biology (2022), 79 (), 4-17CODEN: SECBE7; ISSN:1044-579X. (Elsevier Ltd.)
      A review. Immune checkpoint inhibitors have transformed the prognosis and treatment paradigm of many cancer types, through the potential for durable responses. However, the majority of patients still do not benefit. Response to checkpoint inhibition is detd. by dynamic host, tumor and tumor microenvironment factors that display spatial and temporal variability, but our understanding of these interactions is incomplete. Through investigating biomarkers of resistance and response, opportunities arise to discover new therapeutic targets and shape personalised treatment strategies. Here we review approved and emerging biomarkers of response to immune checkpoint inhibitors, in particular the recent rapid progress in host and tumor genomics. It is unlikely that a single biomarker will precisely predict response, but multivariate multiomic markers may provide a balanced assessment of these factors and more accurately identify patients who will benefit. Further efforts are required to translate these groundbreaking discoveries into novel therapeutics and biomarker driven clin. trials, to provide durable treatment response to a greater population of patients.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtlWqt7jK&md5=17802852fefce3fedc8ce6b596fd7510
    4. 4
      Jenkins, R. W.; Barbie, D. A.; Flaherty, K. T. Mechanisms of Resistance to Immune Checkpoint Inhibitors. Br. J. Cancer 2018, 118, 9– 16,  DOI: 10.1038/bjc.2017.434
      4
      Mechanisms of resistance to immune checkpoint inhibitors
      Jenkins, Russell W.; Barbie, David A.; Flaherty, Keith T.
      British Journal of Cancer (2018), 118 (1), 9-16CODEN: BJCAAI; ISSN:0007-0920. (Nature Research)
      Immune checkpoint inhibitors (ICI) targeting CTLA-4 and the PD-1/PD-L1 axis have shown unprecedented clin. activity in several types of cancer and are rapidly transforming the practice of medical oncol. Whereas cytotoxic chemotherapy and small mol. inhibitors ('targeted therapies') largely act on cancer cells directly, immune checkpoint inhibitors reinvigorate anti-tumor immune responses by disrupting co-inhibitory T-cell signalling. While resistance routinely develops in patients treated with conventional cancer therapies and targeted therapies, durable responses suggestive of long-lasting immunol. memory are commonly seen in large subsets of patients treated with ICI. However, initial response appears to be a binary event, with most non-responders to single-agent ICI therapy progressing at a rate consistent with the natural history of disease. In addn., late relapses are now emerging with longer follow-up of clin. trial populations, suggesting the emergence of acquired resistance. As robust biomarkers to predict clin. response and/or resistance remain elusive, the mechanisms underlying innate (primary) and acquired (secondary) resistance are largely inferred from pre-clin. studies and correlative clin. data. Improved understanding of mol. and immunol. mechanisms of ICI response (and resistance) may not only identify novel predictive and/or prognostic biomarkers, but also ultimately guide optimal combination/sequencing of ICI therapy in the clinic. Here we review the emerging clin. and pre-clin. data identifying novel mechanisms of innate and acquired resistance to immune checkpoint inhibition.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlGmsQ%253D%253D&md5=98d6734fe4172247aa9402fd388159df
    5. 5
      Ye, Z.; Qian, Q.; Jin, H.; Qian, Q. Cancer Vaccine: Learning Lessons from Immune Checkpoint Inhibitors. J. Cancer 2018, 9, 263– 268,  DOI: 10.7150/jca.20059
      5
      Cancer vaccine: learning lessons from immune checkpoint inhibitors
      Ye ZhenLong; Qian Qiming; Jin HuaJun; Qian QiJun
      Journal of Cancer (2018), 9 (2), 263-268 ISSN:1837-9664.
      Cancer vaccines have been exclusively studied all through the past decades, and have made exceptional achievements in cancer treatment. Few cancer vaccines have been approved by the US Food and Drug Administration (FDA), for instance, Provenge, which was approved for the treatment of prostate carcinoma in 2012. Moreover, more recently, T-VEC got approval for the treatment of melanoma. While, the overall therapeutic effects of cancer vaccines have been taken into consideration as below expectations, low antigenicity of targeting antigen and tumor heterogeneity are the two key limiting barriers encountered by the cancer vaccines. Nonetheless, recent developments in cancer immune-therapies together with associated technologies, for instance the unparalleled achievements bagged by immune checkpoint inhibitor based therapies and neo-antigen identification tools, envisage potential improvements in cancer vaccines in respect to the treatments of malignancies. This review brings forth measures for the purpose of refining therapeutic cancer vaccines by learning lessons from the success of PD-1 inhibitor based immune-therapies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MvhslGhtQ%253D%253D&md5=c878c5e7ffce77d94296fce9ae06908a
    6. 6
      Lin, M. J.; Svensson-Arvelund, J.; Lubitz, G. S.; Marabelle, A.; Melero, I.; Brown, B. D.; Brody, J. D. Cancer Vaccines: The Next Immunotherapy Frontier. Nat. Cancer 2022, 3, 911– 926,  DOI: 10.1038/s43018-022-00418-6
      6
      Cancer vaccines: the next immunotherapy frontier
      Lin, Matthew J.; Svensson-Arvelund, Judit; Lubitz, Gabrielle S.; Marabelle, Aurelien; Melero, Ignacio; Brown, Brian D.; Brody, Joshua D.
      Nature Cancer (2022), 3 (8), 911-926CODEN: NCAADQ; ISSN:2662-1347. (Springer International Publishing AG)
      A review. After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other std.-of-care immunotherapies, but they have yet to realize their full potential and expand the oncol. armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clin. development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitlCit7jE&md5=47262a65ec90f090054e453a5bae8b98
    7. 7
      Curran, M. A.; Glisson, B. S. New Hope for Therapeutic Cancer Vaccines in the Era of Immune Checkpoint Modulation. Annu. Rev. Med. 2019, 70, 409– 424,  DOI: 10.1146/annurev-med-050217-121900
      7
      New Hope for Therapeutic Cancer Vaccines in the Era of Immune Checkpoint Modulation
      Curran, Michael A.; Glisson, Bonnie S.
      Annual Review of Medicine (2019), 70 (), 409-424CODEN: ARMCAH; ISSN:0066-4219. (Annual Reviews)
      A review. The driver and passenger mutations accumulated in the process of malignant transformation offer an adequate spectrum of immune visible alterations to the cellular proteome and resulting peptidome to render these cancers targetable-and, in theory, rejectable-by the host T cell immune response. In addn., cancers often overexpress tissue-specific and developmental antigens to which immune tolerance is incomplete. Sometimes, virally transferred oncogenes drive malignant transformation and remain expressed throughout the cancer. Despite this state of antigenic sufficiency, cancer grows progressively and overcomes all efforts of the host immune system to contain it. While therapeutic cancer vaccination can mobilize high frequencies of tumor-specific T cells, these responses remain subject to intratumoral attenuation. Antibody modulation of T cell function through checkpoint blockade or costimulatory activation can restore survival, proliferation, and effector function to these tumor-infiltrating T cells and convert otherwise subtherapeutic vaccines into potentially curative cancer immunotherapeutics.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVGksLzI&md5=58f81e23d229c445006c8672cf6b338b
    8. 8
      Shae, D.; Baljon, J. J.; Wehbe, M.; Becker, K. W.; Sheehy, T. L.; Wilson, J. T. At the Bench: Engineering the Next Generation of Cancer Vaccines. J. Leukoc Biol. 2020, 108, 1435– 1453,  DOI: 10.1002/JLB.5BT0119-016R
      8
      At the bench: Engineering the next generation of cancer vaccines
      Shae, Daniel; Baljon, Jessalyn J.; Wehbe, Mohamed; Becker, Kyle W.; Sheehy, Taylor L.; Wilson, John Tanner
      Journal of Leukocyte Biology (2020), 108 (4), 1435-1453CODEN: JLBIE7; ISSN:1938-3673. (John Wiley & Sons, Inc.)
      A review. Cancer vaccines hold promise as an immunotherapeutic modality based on their potential to generate tumor antigen-specific T cell responses and long-lived antitumor responses capable of combating metastatic disease and recurrence. However, cancer vaccines have historically failed to deliver significant therapeutic benefit in the clinic, which we maintain is due in part to drug delivery challenges that have limited vaccine immunogenicity and efficacy. In this review, we examine some of the known and putative failure mechanisms of common first-generation clin. cancer vaccines, and describe how the rational design of materials engineered for vaccine delivery and immunomodulation can address these shortcomings. First, we outline vaccine design principles for augmenting cellular immunity to tumor antigens and describe how well-engineered materials can improve vaccine efficacy, highlighting recent innovations in vaccine delivery technol. that are primed for integration into neoantigen vaccine development pipelines. We also discuss the importance of sequencing, timing, and kinetics in mounting effective immune responses to cancer vaccines, and highlight examples of materials that potentiate antitumor immunity through spatiotemporal control of immunomodulation. Furthermore, we describe several engineering strategies for improving outcomes of in situ cancer vaccines, which leverage local, intratumoral delivery to stimulate systemic immunity. Finally, we highlight recent innovations leveraging nanotechnol. for increasing the immunogenicity of the tumor microenvironment (TME), which is crit. to enhancing tumor infiltration and function of T cells elicited in response to cancer vaccines. These immunoengineering strategies and tools complement ongoing advances in cancer vaccines as they reemerge as an important component of the immunotherapeutic armamentarium.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhs1ShsrbN&md5=cd67858ef425a0f35c2b527fcf950ea3
    9. 9
      Kleponis, J.; Skelton, R.; Zheng, L. Fueling the Engine and Releasing the Break: Combinational Therapy of Cancer Vaccines and Immune Checkpoint Inhibitors. Cancer Biol. Med. 2015, 12, 201– 208,  DOI: 10.7497/j.issn.2095-3941.2015.0046
      9
      Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors
      Kleponis, Jennifer; Skelton, Richard; Zheng, Lei
      Cancer Biology & Medicine (2015), 12 (3Spec.Iss.), 201-208CODEN: CBMADQ ISSN:. (Tianjin Medical University Cancer Institute and Hospital)
      Immune checkpoint inhibitors are increasingly drawing much attention in the therapeutic development for cancer treatment. However, many cancer patients do not respond to treatments with immune checkpoint inhibitors, partly because of the lack of tumor-infiltrating effector T cells. Cancer vaccines may prime patients for treatments with immune checkpoint inhibitors by inducing effector T-cell infiltration into the tumors and immune checkpoint signals. The combination of cancer vaccine and an immune checkpoint inhibitor may function synergistically to induce more effective antitumor immune responses, and clin. trials to test the combination are currently ongoing.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXlslGjsbY%253D&md5=98c84619ccf7224c4d30882d091a89a5
    10. 10
      Shemesh, C. S.; Hsu, J. C.; Hosseini, I.; Shen, B. Q.; Rotte, A.; Twomey, P.; Girish, S.; Wu, B. Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities. Mol. Ther 2021, 29, 555– 570,  DOI: 10.1016/j.ymthe.2020.09.038
      10
      Personalized Cancer Vaccines: Clinical Landscape, Challenges, and Opportunities
      Shemesh, Colby S.; Hsu, Joy C.; Hosseini, Iraj; Shen, Ben-Quan; Rotte, Anand; Twomey, Patrick; Girish, Sandhya; Wu, Benjamin
      Molecular Therapy (2021), 29 (2), 555-570CODEN: MTOHCK; ISSN:1525-0024. (Cell Press)
      A review. Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8+ and CD4+ T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clin. practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. I.v. or i.m. administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quant. methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXjsVCmsLY%253D&md5=020291133534cc7a2697ae7101562a6c
    11. 11
      Zhao, J.; Chen, Y.; Ding, Z. Y.; Liu, J. Y. Safety and Efficacy of Therapeutic Cancer Vaccines Alone or in Combination with Immune Checkpoint Inhibitors in Cancer Treatment. Front Pharmacol 2019, 10, 1184,  DOI: 10.3389/fphar.2019.01184
      11
      Safety and efficacy of therapeutic cancer vaccines alone or in combination with immune checkpoint inhibitors in cancer treatment
      Zhao, Jing; Chen, Ye; Ding, Zhen-Yu.; Liu, Ji-Yan
      Frontiers in Pharmacology (2019), 10 (), 1184CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
      A review. Therapeutic cancer vaccines have proven to seldom induce dramatic clin. response when used alone, and therefore, they are being studied in combination with addnl. treatment modalities to achieve optimal treatment activities. Growing preclin. data show that combining vaccines and immune checkpoint inhibitors (ICIs) can prime intensified immunogenicity and modulate immunosuppressive tumor microenvironment. Herein, we focus on the safety and efficacy of approved and promising cancer vaccines alone or combined with ICIs in the treatment of several malignancies. Generally, the majority of clin. trials support the concept of synergy that combination therapy of vaccines and ICIs holds maximized potential to improve clin. outcomes. Importantly, the combination has acceptable safety and minimal addnl. toxicity compared with single-agent vaccines or ICIs. Addnl., the potential strategies of combining personalized tumor vaccines with ICIs will become priority option and future direction of vaccine development and application and the urgent need to develop effective biomarkers to screen appropriate patient populations and predict response to combination therapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpvVeqtLk%253D&md5=b9137c6f5bd286e8db5eb610319bab4b
    12. 12
      Blass, E.; Ott, P. A. Advances in the Development of Personalized Neoantigen-Based Therapeutic Cancer Vaccines. Nat. Rev. Clin Oncol 2021, 18, 215– 229,  DOI: 10.1038/s41571-020-00460-2
      12
      Advances in the development of personalized neoantigen-based therapeutic cancer vaccines
      Blass Eryn; Ott Patrick A; Ott Patrick A; Ott Patrick A; Ott Patrick A
      Nature reviews. Clinical oncology (2021), 18 (4), 215-229 ISSN:.
      Within the past decade, the field of immunotherapy has revolutionized the treatment of many cancers with the development and regulatory approval of various immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies in diverse indications. Another promising approach to cancer immunotherapy involves the use of personalized vaccines designed to trigger de novo T cell responses against neoantigens, which are highly specific to tumours of individual patients, in order to amplify and broaden the endogenous repertoire of tumour-specific T cells. Results from initial clinical studies of personalized neoantigen-based vaccines, enabled by the availability of rapid and cost-effective sequencing and bioinformatics technologies, have demonstrated robust tumour-specific immunogenicity and preliminary evidence of antitumour activity in patients with melanoma and other cancers. Herein, we provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, review the types of vaccine-induced T cells that are found within tumours and outline strategies to enhance the T cell responses. In addition, we discuss the current status of clinical studies testing personalized neoantigen vaccines in patients with cancer and considerations for future clinical investigation of this novel, individualized approach to immunotherapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3srivFOqtQ%253D%253D&md5=82c721ffe87a85367bc1081598d18a5d
    13. 13
      Schumacher, T. N.; Scheper, W.; Kvistborg, P. Cancer Neoantigens. Annu. Rev. Immunol. 2019, 37, 173– 200,  DOI: 10.1146/annurev-immunol-042617-053402
      13
      Cancer Neoantigens
      Schumacher, Ton N.; Scheper, Wouter; Kvistborg, Pia
      Annual Review of Immunology (2019), 37 (), 173-200CODEN: ARIMDU; ISSN:0732-0582. (Annual Reviews)
      A review. Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell-based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clin. activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biol. properties of these antigens. We discuss recent technol. advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clin. interventions.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFejsLfP&md5=21b8e70354a6e489f6f56f526f2f08ba
    14. 14
      Janes, M. E.; Gottlieb, A. P.; Park, K. S.; Zhao, Z.; Mitragotri, S. Cancer Vaccines in the Clinic. Bioeng Transl Med. 2024, 9, e10588  DOI: 10.1002/btm2.10588
      There is no corresponding record for this reference.
    15. 15
      Baljon, J. J.; Wilson, J. T. Bioinspired Vaccines to Enhance Mhc Class-I Antigen Cross-Presentation. Curr. Opin Immunol 2022, 77, 102215,  DOI: 10.1016/j.coi.2022.102215
      15
      Bioinspired vaccines to enhance MHC class-I antigen cross-presentation
      Baljon, Jessalyn J.; Wilson, John T.
      Current Opinion in Immunology (2022), 77 (), 102215CODEN: COPIEL; ISSN:0952-7915. (Elsevier Ltd.)
      A review. Here, we briefly summarize known cross-presentation pathways and highlight how synthetic vaccines can be engineered to enhance MHC-I presentation of exogenous peptide and protein antigens by professional antigen-presenting cells (APCs). In particular, we summarize how mol. engineering and nanotechnol. are being harnessed to enhance antigen delivery to lymph nodes and to cross-presenting dendritic cells, to bypass endosomal trafficking of exogenous antigen to promote delivery of antigen to the cytosol of APCs, and to coordinate the delivery of antigen with immune-stimulating adjuvants that can act synergistically to augment antigen cross-presentation. Cross-presentation of exogenous antigen on MHC class-I is a crucial process for generating a CD8+ T cell response, and is therefore an important design consideration in the development of T-cell-engaging vaccines against viruses, intracellular bacteria, and cancers.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhtl2jtr7M&md5=66ac8dde3eed78c8f43ac96caae336fe
    16. 16
      Liu, W.; Tang, H.; Li, L.; Wang, X.; Yu, Z.; Li, J. Peptide-Based Therapeutic Cancer Vaccine: Current Trends in Clinical Application. Cell Prolif 2021, 54, e13025  DOI: 10.1111/cpr.13025
      16
      Peptide-based therapeutic cancer vaccine: Current trends in clinical application
      Liu, Wensi; Tang, Haichao; Li, Luanfeng; Wang, Xiangyi; Yu, Zhaojin; Li, Jianping
      Cell Proliferation (2021), 54 (5), e13025CODEN: CPROEM; ISSN:0960-7722. (John Wiley & Sons Ltd.)
      A review. The peptide-based therapeutic cancer vaccines have attracted enormous attention in recent years as one of the effective treatments of tumor immunotherapy. Most of peptide-based vaccines are based on epitope peptides stimulating CD8+ T cells or CD4+ T helper cells to target tumor-assocd. antigens (TAAs) or tumor-specific antigens (TSAs). Some adjuvants and nanomaterials have been exploited to optimize the efficiency of immune response of the epitope peptide to improve its clin. application. At present, numerous peptide-based therapeutic cancer vaccines have been developed and achieved significant clin. benefits. Similarly, the combination of peptide-based vaccines and other therapies has demonstrated a superior efficacy in improving anti-cancer activity. We delve deeper into the choices of targets, design and screening of epitope peptides, clin. efficacy and adverse events of peptide-based vaccines, and strategies combination of peptide-based therapeutic cancer vaccines and other therapies. The review will provide a detailed overview and basis for future clin. application of peptide-based therapeutic cancer vaccines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtVWrtLfK&md5=00a6a94c14b8864a77e1fcce50f5f785
    17. 17
      Stephens, A. J.; Burgess-Brown, N. A.; Jiang, S. Beyond Just Peptide Antigens: The Complex World of Peptide-Based Cancer Vaccines. Front Immunol 2021, 12, 696791,  DOI: 10.3389/fimmu.2021.696791
      17
      Beyond just peptide antigens: the complex world of peptide-based cancer vaccines
      Stephens, Alexander J.; Burgess-Brown, Nicola A.; Jiang, Shisong
      Frontiers in Immunology (2021), 12 (), 696791CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
      A review. Peptide-based cancer vaccines rely upon the strong activation of the adaptive immune response to elicit its effector function. They have shown to be highly specific and safe, but have yet to prove themselves as an efficacious treatment for cancer in the clinic. This is for a variety of reasons, including tumor heterogeneity, self-tolerance, and immune suppression. Importance has been placed on the overall design of peptide-based cancer vaccines, which have evolved from simple peptide derivs. of a cancer antigen, to complex drugs; incorporating overlapping regions, conjugates, and delivery systems to target and stimulate different components of antigen presenting cells, and to bolster antigen cross-presentation. Peptide-based cancer vaccines are increasingly becoming more personalised to an individuals tumor antigen repertoire and are often combined with existing cancer treatments. This strategy ultimately aids in combating the shortcomings of a more generalised vaccine strategy and provides a comprehensive treatment, taking into consideration cancer cell variability and its ability to avoid immune interrogation.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhvFOitrvK&md5=d642fe90d7d555cd18312a800d8be80f
    18. 18
      Yewdell, J. W. Designing CD8+ T Cell Vaccines: It’s Not Rocket Science (Yet). Curr. Opin Immunol 2010, 22, 402– 410,  DOI: 10.1016/j.coi.2010.04.002
      18
      Designing CD8+ T cell vaccines: it's not rocket science (yet)
      Yewdell, Jonathan W.
      Current Opinion in Immunology (2010), 22 (3), 402-410CODEN: COPIEL; ISSN:0952-7915. (Elsevier B.V.)
      A review. CD8+ T cells play important roles in clearing viral infections and eradicating tumors. Designing vaccines that elicit effective CD8+ T cell responses requires a thorough knowledge of the pathways of antigen presentation in vivo. Here, I review recent progress in understanding the activation of naive CD8+ T cells in vivo, with particular emphasis on cross-priming, the presentation of protein antigens acquired by dendritic cells from their environment. With the rapid advances in this area of research, the dawn of rational vaccine design is at hand.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXntV2jsbk%253D&md5=f6f6853cd382fab6b98cb14088f25b2f
    19. 19
      Khong, H.; Overwijk, W. W. Adjuvants for Peptide-Based Cancer Vaccines. J. Immunother Cancer 2016, 4, 56,  DOI: 10.1186/s40425-016-0160-y
      19
      Adjuvants for peptide-based cancer vaccines
      Khong Hiep; Overwijk Willem W
      Journal for immunotherapy of cancer (2016), 4 (), 56 ISSN:2051-1426.
      Cancer therapies based on T cells have shown impressive clinical benefit. In particular, immune checkpoint blockade therapies with anti-CTLA-4 and anti-PD-1/PD-L1 are causing dramatic tumor shrinkage and prolonged patient survival in a variety of cancers. However, many patients do not benefit, possibly due to insufficient spontaneous T cell reactivity against their tumors and/or lacking immune cell infiltration to tumor site. Such tumor-specific T cell responses could be induced through anti-cancer vaccination; but despite great success in animal models, only a few of many cancer vaccine trials have demonstrated robust clinical benefit. One reason for this difference may be the use of potent, effective vaccine adjuvants in animal models, vs. the use of safe, but very weak, vaccine adjuvants in clinical trials. As vaccine adjuvants dictate the type and magnitude of the T cell response after vaccination, it is critical to understand how they work to design safe, but also effective, cancer vaccines for clinical use. Here we discuss current insights into the mechanism of action and practical application of vaccine adjuvants, with a focus on peptide-based cancer vaccines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svjtl2ntw%253D%253D&md5=caffd368c197f407b12a8b1264be8038
    20. 20
      Gouttefangeas, C.; Rammensee, H. G. Personalized Cancer Vaccines: Adjuvants Are Important, Too. Cancer Immunol Immunother 2018, 67, 1911– 1918,  DOI: 10.1007/s00262-018-2158-4
      20
      Personalized cancer vaccines: adjuvants are important, too
      Gouttefangeas, Cecile; Rammensee, Hans-Georg
      Cancer Immunology Immunotherapy (2018), 67 (12), 1911-1918CODEN: CIIMDN; ISSN:0340-7004. (Springer)
      Therapeutic cancer vaccines have shown limited clin. efficacy so far. Nevertheless, in the meantime, our understanding of immune cell function and the interactions of immune cells with growing tumors has advanced considerably. We are now in a position to invest this knowledge into the design of more powerful vaccines and therapy combinations aimed at increasing immunogenicity and decreasing tumor-induced immunosuppression. This review focuses essentially on peptide-based human vaccines. We will discuss two aspects that are crit. for increasing their intrinsic immunogenicity: the selection of the antigen(s) to be targeted, and the as yet unmet need for strong adjuvants.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXnsVGqsrc%253D&md5=f0bb1792ca78fcf2e11b427377a3cd44
    21. 21
      Temizoz, B.; Kuroda, E.; Ishii, K. J. Vaccine Adjuvants as Potential Cancer Immunotherapeutics. Int. Immunol. 2016, 28, 329– 338,  DOI: 10.1093/intimm/dxw015
      21
      Vaccine adjuvants as potential cancer immunotherapeutics
      Temizoz, Burcu; Kuroda, Etsushi; Ishii, Ken J.
      International Immunology (2016), 28 (7), 329-338CODEN: INIMEN; ISSN:0953-8178. (Oxford University Press)
      Accumulated evidence obtained from various clin. trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clin. trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsFOru7fE&md5=92aa03134406c55673017cb24da45eb4
    22. 22
      Kaur, A.; Baldwin, J.; Brar, D.; Salunke, D. B.; Petrovsky, N. Toll-Like Receptor (TLR) Agonists as a Driving Force Behind Next-Generation Vaccine Adjuvants and Cancer Therapeutics. Curr. Opin Chem. Biol. 2022, 70, 102172,  DOI: 10.1016/j.cbpa.2022.102172
      22
      Toll-like receptor (TLR) agonists as a driving force behind next-generation vaccine adjuvants and cancer therapeutics
      Kaur, Arshpreet; Baldwin, Jeremy; Brar, Deshkanwar; Salunke, Deepak B.; Petrovsky, Nikolai
      Current Opinion in Chemical Biology (2022), 70 (), 102172CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
      A review until recently, the development of new human adjuvants was held back by a poor understanding of their mechanisms of action. The field was revolutionized by the discovery of the toll-like receptors (TLRs), innate immune receptors that directly or indirectly are responsible for detecting pathogen-assocd. mol. patterns (PAMPs) and respond to them by activating innate and adaptive immune pathways. Hundreds of ligands targeting various TLRs have since been identified and characterized as vaccine adjuvants. This work has important implications not only for the development of vaccines against infectious diseases but also for immuno-therapies against cancer, allergy, Alzheimer's disease, drug addiction and other diseases. Each TLR has its own specific tissue localization and downstream gene pathways, providing researchers the opportunity to precisely tailor adjuvants with specific immune effects. TLR agonists can be combined with other TLR or alternative adjuvants to create combination adjuvants with synergistic or modulatory effects. This review provides an introduction to the various classes of TLR adjuvants and their resp. pathways. It provides an overview of recent advancements in the TLR field in the past 2-3 years and discusses criteria for selecting specific TLR adjuvants based on considerations, such as disease mechanisms and correlates of protection, TLR immune biasing capabilities, route of administration, antigen compatibility, new vaccine technol. platforms, and age- and species-specific effects.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xhs1yitbnL&md5=3150d579bdb7406e044934c74a7af2cd
    23. 23
      Hu, H. G.; Li, Y. M. Emerging Adjuvants for Cancer Immunotherapy. Front Chem. 2020, 8, 601,  DOI: 10.3389/fchem.2020.00601
      23
      Emerging adjuvants for cancer immunotherapy
      Hu, Hong-Guo; Li, Yan-Mei
      Frontiers in Chemistry (Lausanne, Switzerland) (2020), 8 (), 601CODEN: FCLSAA; ISSN:2296-2646. (Frontiers Media S.A.)
      A review. Cancer is a life-threatening disease, and immunotherapies have been developed as a novel, potent treatment for cancer. Adjuvants, used alone or in combination with other agents, play crucial roles in immune activation. This is necessary for cancer immunotherapy, particularly in the construction of therapeutic cancer vaccines. Adjuvants activate antigen-presenting cells and promote the presentation of antigen epitopes on major histocompatibility complex mols., further enhancing adaptive immune responses, including cytotoxic T lymphocytes, to elicit cancer-cell death. However, the applications of adjuvants are limited by their poor efficacy or insufficient safety. In recent studies, researchers attempted to develop safe, efficacious adjuvants for cancer immunotherapy, and many compds. (including inorg. compds., org. mols., polymers, and colloids) have been identified and optimized as agonists of various pathways. In this , we focus on the discovery and structural design of emerging adjuvants and discuss how these findings benefit healthcare.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFWit7vF&md5=03aa3cb231a4e3245efde5c3e6959b61
    24. 24
      Paston, S. J.; Brentville, V. A.; Symonds, P.; Durrant, L. G. Cancer Vaccines, Adjuvants, and Delivery Systems. Front Immunol 2021, 12, 627932,  DOI: 10.3389/fimmu.2021.627932
      24
      Cancer vaccines, adjuvants, and delivery systems
      Paston, Samantha j.; Brentville, Victoria a.; Symonds, Peter; Durrant, Lindy g.
      Frontiers in Immunology (2021), 12 (), 627932CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
      A review. Vaccination was first pioneered in the 18th century by Edward Jenner and eventually led to the development of the smallpox vaccine and subsequently the eradication of smallpox. The impact of vaccination to prevent infectious diseases has been outstanding with many infections being prevented and a significant decrease in mortality worldwide. Cancer vaccines aim to clear active disease instead of aiming to prevent disease, the only exception being the recently approved vaccine that prevents cancers caused by the Human Papillomavirus. The development of therapeutic cancer vaccines has been disappointing with many early cancer vaccines that showed promise in preclin. models often failing to translate into efficacy in the clinic. In this review we provide an overview of the current vaccine platforms, adjuvants and delivery systems that are currently being investigated or have been approved. With the advent of immune checkpoint inhibitors, we also review the potential of these to be used with cancer vaccines to improve efficacy and help to overcome the immune suppressive tumor microenvironment.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXpvVyhtrg%253D&md5=3d9e90696dda37b5ab117b67a282262d
    25. 25
      Keskin, D. B.; Anandappa, A. J.; Sun, J.; Tirosh, I.; Mathewson, N. D.; Li, S.; Oliveira, G.; Giobbie-Hurder, A.; Felt, K.; Gjini, E. Neoantigen Vaccine Generates Intratumoral T Cell Responses in Phase Ib Glioblastoma Trial. Nature 2019, 565, 234– 239,  DOI: 10.1038/s41586-018-0792-9
      25
      Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial
      Keskin, Derin B.; Anandappa, Annabelle J.; Sun, Jing; Tirosh, Itay; Mathewson, Nathan D.; Li, Shuqiang; Oliveira, Giacomo; Giobbie-Hurder, Anita; Felt, Kristen; Gjini, Evisa; Shukla, Sachet A.; Hu, Zhuting; Li, Letitia; Le, Phuong M.; Allesoee, Rosa L.; Richman, Alyssa R.; Kowalczyk, Monika S.; Abdelrahman, Sara; Geduldig, Jack E.; Charbonneau, Sarah; Pelton, Kristine; Iorgulescu, J. Bryan; Elagina, Liudmila; Zhang, Wandi; Olive, Oriol; McCluskey, Christine; Olsen, Lars R.; Stevens, Jonathan; Lane, William J.; Salazar, Andres M.; Daley, Heather; Wen, Patrick Y.; Chiocca, E. Antonio; Harden, Maegan; Lennon, Niall J.; Gabriel, Stacey; Getz, Gad; Lander, Eric S.; Regev, Aviv; Ritz, Jerome; Neuberg, Donna; Rodig, Scott J.; Ligon, Keith L.; Suva, Mario L.; Wucherpfennig, Kai W.; Hacohen, Nir; Fritsch, Edward F.; Livak, Kenneth J.; Ott, Patrick A.; Wu, Catherine J.; Reardon, David A.
      Nature (London, United Kingdom) (2019), 565 (7738), 234-239CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      Neoantigens, which are derived from tumor-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumor rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumors such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunol. 'cold' tumor microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral edema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the no. of tumor-infiltrating T cells. Using single-cell T cell receptor anal., we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumor. Neoantigen-targeting vaccines thus have the potential to favorably alter the immune milieu of glioblastoma.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFyksLvE&md5=665425d605411ebfd4764314e7d1f220
    26. 26
      Ott, P. A.; Hu, Z.; Keskin, D. B.; Shukla, S. A.; Sun, J.; Bozym, D. J.; Zhang, W.; Luoma, A.; Giobbie-Hurder, A.; Peter, L.; Chen, C.; Olive, O.; Carter, T. A.; Li, S.; Lieb, D. J.; Eisenhaure, T.; Gjini, E.; Stevens, J.; Lane, W. J.; Javeri, I. An Immunogenic Personal Neoantigen Vaccine for Patients with Melanoma. Nature 2017, 547, 217– 221,  DOI: 10.1038/nature22991
      26
      An immunogenic personal neoantigen vaccine for patients with melanoma
      Ott, Patrick A.; Hu, Zhuting; Keskin, Derin B.; Shukla, Sachet A.; Sun, Jing; Bozym, David J.; Zhang, Wandi; Luoma, Adrienne; Giobbie-Hurder, Anita; Peter, Lauren; Chen, Christina; Olive, Oriol; Carter, Todd A.; Li, Shuqiang; Lieb, David J.; Eisenhaure, Thomas; Gjini, Evisa; Stevens, Jonathan; Lane, William J.; Javeri, Indu; Nellaiappan, Kaliappanadar; Salazar, Andres M.; Daley, Heather; Seaman, Michael; Buchbinder, Elizabeth I.; Yoon, Charles H.; Harden, Maegan; Lennon, Niall; Gabriel, Stacey; Rodig, Scott J.; Barouch, Dan H.; Aster, Jon C.; Getz, Gad; Wucherpfennig, Kai; Neuberg, Donna; Ritz, Jerome; Lander, Eric S.; Fritsch, Edward F.; Hacohen, Nir; Wu, Catherine J.
      Nature (London, United Kingdom) (2017), 547 (7662), 217-221CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      Effective anti-tumor immunity in humans has been assocd. with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumor-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumor immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumors, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) mols. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoral balance in favor of enhanced tumor control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumor neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, resp. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumor. Of six vaccinated patients, four had no recurrence at 25 mo after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumor regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFaqt7rO&md5=e235523b95d4f6ae4aeceb1047460ab3
    27. 27
      Swartz, M. A.; Hirosue, S.; Hubbell, J. A. Engineering Approaches to Immunotherapy. Science Translational Medicine 2012, 4, 148rv149,  DOI: 10.1126/scitranslmed.3003763
      There is no corresponding record for this reference.
    28. 28
      Knight, F. C.; Gilchuk, P.; Kumar, A.; Becker, K. W.; Sevimli, S.; Jacobson, M. E.; Suryadevara, N.; Wang-Bishop, L.; Boyd, K. L.; Crowe, J. E., Jr.; Joyce, S.; Wilson, J. T. Mucosal Immunization with a pH-Responsive Nanoparticle Vaccine Induces Protective CD8(+) Lung-Resident Memory T Cells. ACS Nano 2019, 13, 10939– 10960,  DOI: 10.1021/acsnano.9b00326
      28
      Mucosal Immunization with a pH-Responsive Nanoparticle Vaccine Induces Protective CD8+ Lung-Resident Memory T Cells
      Knight, Frances C.; Gilchuk, Pavlo; Kumar, Amrendra; Becker, Kyle W.; Sevimli, Sema; Jacobson, Max E.; Suryadevara, Naveenchandra; Wang-Bishop, Lihong; Boyd, Kelli L.; Crowe, James E.; Joyce, Sebastian; Wilson, John T.
      ACS Nano (2019), 13 (10), 10939-10960CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Tissue-resident memory T cells (TRM) patrol nonlymphoid organs and provide superior protection against pathogens that commonly infect mucosal and barrier tissues, such as the lungs, intestine, liver, and skin. Thus, there is a need for vaccine technologies that can induce a robust, protective TRM response in these tissues. Nanoparticle (NP) vaccines offer important advantages over conventional vaccines; however, there has been minimal investigation into the design of NP-based vaccines for eliciting TRM responses. Here, we describe a pH-responsive polymeric nanoparticle vaccine for generating antigen-specific CD8+ TRM cells in the lungs. With a single intranasal dose, the NP vaccine elicited airway- and lung-resident CD8+ TRM cells and protected against respiratory virus challenge in both sublethal (vaccinia) and lethal (influenza) infection models for up to 9 wk after immunization. In elucidating the contribution of material properties to the resulting TRM response, we found that the pH-responsive activity of the carrier was important, as a structurally analogous non-pH-responsive control carrier elicited significantly fewer lung-resident CD8+ T cells. We also demonstrated that dual-delivery of protein antigen and nucleic acid adjuvant on the same NP substantially enhanced the magnitude, functionality, and longevity of the antigen-specific CD8+ TRM response in the lungs. Compared to administration of sol. antigen and adjuvant, the NP also mediated retention of vaccine cargo in pulmonary antigen-presenting cells (APCs), enhanced APC activation, and increased prodn. of TRM-related cytokines. Overall, these data suggest a promising vaccine platform technol. for rapid generation of protective CD8+ TRM cells in the lungs.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvVCnt7%252FO&md5=44662b0a177490dcb700c98b7fd56e5e
    29. 29
      Kuai, R.; Ochyl, L. J.; Bahjat, K. S.; Schwendeman, A.; Moon, J. J. Designer Vaccine Nanodiscs for Personalized Cancer Immunotherapy. Nat. Mater. 2017, 16, 489– 496,  DOI: 10.1038/nmat4822
      29
      Designer vaccine nanodiscs for personalized cancer immunotherapy
      Kuai, Rui; Ochyl, Lukasz J.; Bahjat, Keith S.; Schwendeman, Anna; Moon, James J.
      Nature Materials (2017), 16 (4), 489-496CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
      Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumor exome sequencing have signalled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodol. for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high-d. lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than sol. vaccines and even 31-fold greater than perhaps the strongest adjuvant in clin. trials (i.e., CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumor growth. Nanodiscs eliminated established MC-38 and B16F10 tumors when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitFGitLvO&md5=247bc6ef1a21f3a1bce8addcbb7a6a0d
    30. 30
      Li, A. W.; Sobral, M. C.; Badrinath, S.; Choi, Y.; Graveline, A.; Stafford, A. G.; Weaver, J. C.; Dellacherie, M. O.; Shih, T. Y.; Ali, O. A.; Kim, J.; Wucherpfennig, K. W.; Mooney, D. J. A Facile Approach to Enhance Antigen Response for Personalized Cancer Vaccination. Nat. Mater. 2018, 17, 528– 534,  DOI: 10.1038/s41563-018-0028-2
      30
      A facile approach to enhance antigen response for personalized cancer vaccination
      Li, Aileen Weiwei; Sobral, Miguel C.; Badrinath, Soumya; Choi, Youngjin; Graveline, Amanda; Stafford, Alexander G.; Weaver, James C.; Dellacherie, Maxence O.; Shih, Ting-Yu; Ali, Omar A.; Kim, Jaeyun; Wucherpfennig, Kai W.; Mooney, David J.
      Nature Materials (2018), 17 (6), 528-534CODEN: NMAACR; ISSN:1476-1122. (Nature Research)
      Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which, beyond practical issues, may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica microrod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T-cell response over the existing MSR vaccine and bolus vaccine formulations. Impressively, a single injection of the MSR-PEI vaccine using an E7 peptide completely eradicated large, established TC-1 tumors in about 80% of mice and generated immunol. memory. When immunized with a pool of B16F10 or CT26 neoantigens, the MSR-PEI vaccine eradicated established lung metastases, controlled tumor growth and synergized with anti-CTLA4 therapy. Our findings from three independent tumor models suggest that the MSR-PEI vaccine approach may serve as a facile and powerful multi-antigen platform to enable robust personalized cancer vaccination.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXltFOrsrs%253D&md5=3723b6388b35a6a546eb78ace8db9e9f
    31. 31
      Liu, H.; Moynihan, K. D.; Zheng, Y.; Szeto, G. L.; Li, A. V.; Huang, B.; Van Egeren, D. S.; Park, C.; Irvine, D. J. Structure-Based Programming of Lymph-Node Targeting in Molecular Vaccines. Nature 2014, 507, 519– 522,  DOI: 10.1038/nature12978
      31
      Structure-based programming of lymph-node targeting in molecular vaccines
      Liu, Haipeng; Moynihan, Kelly D.; Zheng, Yiran; Szeto, Gregory L.; Li, Adrienne V.; Huang, Bonnie; Van Egeren, Debra S.; Park, Clara; Irvine, Darrell J.
      Nature (London, United Kingdom) (2014), 507 (7493), 519-522CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compds. to LNs, where they are efficiently filtered by resident phagocytes. Here we translate this 'albumin hitchhiking' approach to mol. vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a soly.-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compds., leading to 30-fold increases in T-cell priming and enhanced anti-tumor efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXkvV2ru70%253D&md5=2890c3d27d8b989930052ba6bbed3294
    32. 32
      Lynn, G. M.; Sedlik, C.; Baharom, F.; Zhu, Y.; Ramirez-Valdez, R. A.; Coble, V. L.; Tobin, K.; Nichols, S. R.; Itzkowitz, Y.; Zaidi, N.; Gammon, J. M.; Blobel, N. J.; Denizeau, J.; de la Rochere, P.; Francica, B. J.; Decker, B.; Maciejewski, M.; Cheung, J.; Yamane, H.; Smelkinson, M. G. Peptide-TLR-7/8a Conjugate Vaccines Chemically Programmed for Nanoparticle Self-Assembly Enhance CD8 T-Cell Immunity to Tumor Antigens. Nat. Biotechnol. 2020, 38, 320– 332,  DOI: 10.1038/s41587-019-0390-x
      32
      Peptide-TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens
      Lynn, Geoffrey M.; Sedlik, Christine; Baharom, Faezzah; Zhu, Yaling; Ramirez-Valdez, Ramiro A.; Coble, Vincent L.; Tobin, Kennedy; Nichols, Sarah R.; Itzkowitz, Yaakov; Zaidi, Neeha; Gammon, Joshua M.; Blobel, Nicolas J.; Denizeau, Jordan; de la Rochere, Philippe; Francica, Brian J.; Decker, Brennan; Maciejewski, Mateusz; Cheung, Justin; Yamane, Hidehiro; Smelkinson, Margery G.; Francica, Joseph R.; Laga, Richard; Bernstock, Joshua D.; Seymour, Leonard W.; Drake, Charles G.; Jewell, Christopher M.; Lantz, Olivier; Piaggio, Eliane; Ishizuka, Andrew S.; Seder, Robert A.
      Nature Biotechnology (2020), 38 (3), 320-332CODEN: NABIF9; ISSN:1087-0156. (Nature Research)
      Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochem. variability can present challenges to manufg. personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chem. programmed to self-assemble into nanoparticles of uniform size (∼20 nm) irresp. of the peptide antigen compn. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ∼50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXotFGltw%253D%253D&md5=2b4321aa1d0eec8e7a4b2d5aca33a648
    33. 33
      Shae, D.; Baljon, J. J.; Wehbe, M.; Christov, P. P.; Becker, K. W.; Kumar, A.; Suryadevara, N.; Carson, C. S.; Palmer, C. R.; Knight, F. C.; Joyce, S.; Wilson, J. T. Co-Delivery of Peptide Neoantigens and Stimulator of Interferon Genes Agonists Enhances Response to Cancer Vaccines. ACS Nano 2020, 14, 9904– 9916,  DOI: 10.1021/acsnano.0c02765
      33
      Co-delivery of Peptide Neoantigens and Stimulator of Interferon Genes Agonists Enhances Response to Cancer Vaccines
      Shae, Daniel; Baljon, Jessalyn J.; Wehbe, Mohamed; Christov, Plamen P.; Becker, Kyle W.; Kumar, Amrendra; Suryadevara, Naveenchandra; Carson, Carcia S.; Palmer, Christian R.; Knight, Frances C.; Joyce, Sebastian; Wilson, John T.
      ACS Nano (2020), 14 (8), 9904-9916CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Cancer vaccines targeting patient-specific neoantigens have emerged as a promising strategy for improving responses to immune checkpoint blockade. However, neoantigenic peptides are poorly immunogenic and inept at stimulating CD8+ T cell responses, motivating a need for new vaccine technologies that enhance their immunogenicity. The stimulator of interferon genes (STING) pathway is an endogenous mechanism by which the innate immune system generates an immunol. context for priming and mobilizing neoantigen-specific T cells. Owing to this crit. role in tumor immune surveillance, a synthetic cancer nanovaccine platform (nanoSTING-vax) was developed that mimics immunogenic cancer cells in its capacity to efficiently promote co-delivery of peptide antigens and the STING agonist, cGAMP. The co-loading of cGAMP and peptides into pH-responsive, endosomolytic polymersomes promoted the coordinated delivery of both cGAMP and peptide antigens to the cytosol, thereby eliciting inflammatory cytokine prodn., co-stimulatory marker expression, and antigen cross-presentation. Consequently, nanoSTING-vax significantly enhanced CD8+ T cell responses to a range of peptide antigens. Therapeutic immunization with nanoSTING-vax, in combination with immune checkpoint blockade, inhibited tumor growth in multiple murine tumor models, even leading to complete tumor rejection and generation of durable antitumor immune memory. Collectively, this work establishes nanoSTING-vax as a versatile platform for enhancing immune responses to neoantigen-targeted cancer vaccines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVCmsLjL&md5=e52e9db129f9916ccbb51b96ead541fc
    34. 34
      Tornesello, A. L.; Tagliamonte, M.; Tornesello, M. L.; Buonaguro, F. M.; Buonaguro, L. Nanoparticles to Improve the Efficacy of Peptide-Based Cancer Vaccines. Cancers (Basel) 2020, 12, 1049,  DOI: 10.3390/cancers12041049
      There is no corresponding record for this reference.
    35. 35
      Viswanath, D. I.; Liu, H. C.; Huston, D. P.; Chua, C. Y. X.; Grattoni, A. Emerging Biomaterial-Based Strategies for Personalized Therapeutic in Situ Cancer Vaccines. Biomaterials 2022, 280, 121297,  DOI: 10.1016/j.biomaterials.2021.121297
      35
      Emerging biomaterial-based strategies for personalized therapeutic in situ cancer vaccines
      Viswanath, Dixita Ishani; Liu, Hsuan-Chen; Huston, David P.; Chua, Corrine Ying Xuan; Grattoni, Alessandro
      Biomaterials (2022), 280 (), 121297CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      A review. Landmark successes in oncoimmunol. have led to development of therapeutics boosting the host immune system to eradicate local and distant tumors with impactful tumor redn. in a subset of patients. However, current immunotherapy modalities often demonstrate limited success when involving immunol. cold tumors and solid tumors. Here, we describe the role of various biomaterials to formulate cancer vaccines as a form of cancer immunotherapy, seeking to utilize the host immune system to activate and expand tumor-specific T cells. Biomaterial-based cancer vaccines enhance the cancer-immunity cycle by harnessing cellular recruitment and activation against tumor-specific antigens. In this review, we discuss biomaterial-based vaccine strategies to induce lymphocytic responses necessary to mediate anti-tumor immunity. We focus on strategies that selectively attract dendritic cells via immunostimulatory gradients, activate them against presented tumor-specific antigens, and induce effective cross-presentation to T cells in secondary lymphoid organs, thereby generating immunity. We posit that personalized cancer vaccines are promising targets to generate long-term systemic immunity against patient- and tumor-specific antigens to ensure long-term cancer remission.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXislWkurfI&md5=6c16a058af7c31ba986ce1a85033ee82
    36. 36
      Wu, S.; Xia, Y.; Hu, Y.; Ma, G. Bio-Mimic Particles for the Enhanced Vaccinations: Lessons Learnt from the Natural Traits and Pathogenic Invasion. Adv. Drug Deliv Rev. 2021, 176, 113871,  DOI: 10.1016/j.addr.2021.113871
      36
      Bio-mimic particles for the enhanced vaccinations: Lessons learnt from the natural traits and pathogenic invasion
      Wu, Sihua; Xia, Yufei; Hu, Yuning; Ma, Guanghui
      Advanced Drug Delivery Reviews (2021), 176 (), 113871CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      A review. In the combat against pathogens, the immune systems were evolved with the immune recognitions against the various danger signals, which responded vigorously upon the pathogen invasions and elicited potent antibodies or T cell engagement against the re-infections. Envisage with the prevailing pandemics and increasing demands for cancer vaccines, bio-mimic particles were developed to imitate the natural traits of the pathogens, which conferred the optimal strategies to stimulate the immune engagement and let to the increased vaccine efficacy. Here, the recent development in bio-mimic particles, as well as the natural cues from the pathogens were discussed. As such, the designing principles that adapted from the physiochem. properties of the pathogens were unfolded as the surface characteristics (hydrophobic, nano-pattern, antigen display, charge), properties (size, shape, softness) and the delivered components (peptide, protein, nuclear acids, toll-like receptor (TLR) agonist, antibody). Addnl., the strategies for the efficient delivery, regarding the biodistribution, internalization and presentation of the antigens were also illustrated. Through reviewing the state-of-art in biomimetic particles, the lesson learnt from the natural traits and pathogenic invasion may shed light on the rational design for the enhanced vaccinations.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhs1KgsL7O&md5=106fa4408f1ebb0c26ae41f4a4c8df36
    37. 37
      Rosenthal, J. A.; Chen, L.; Baker, J. L.; Putnam, D.; DeLisa, M. P. Pathogen-Like Particles: Biomimetic Vaccine Carriers Engineered at the Nanoscale. Curr. Opin Biotechnol 2014, 28, 51– 58,  DOI: 10.1016/j.copbio.2013.11.005
      37
      Pathogen-like particles: biomimetic vaccine carriers engineered at the nanoscale
      Rosenthal, Joseph A.; Chen, Linxiao; Baker, Jenny L.; Putnam, David; DeLisa, Matthew P.
      Current Opinion in Biotechnology (2014), 28 (), 51-58CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
      Vaccine adjuvants are an essential component of vaccine design, helping to generate immunity to pathogen antigens in the absence of infection. Recent advances in nanoscale engineering have created a new class of particulate bionanotechnol. that uses biomimicry to better integrate adjuvant and antigen. These pathogen-like particles, or PLPs, can come from a variety of sources, ranging from fully synthetic platforms to biol. derived, self-assembling systems. By employing molecularly engineered targeting and stimulation of key immune cells, recent studies utilizing PLPs as vaccine delivery platforms have shown great promise against high-impact, unsolved vaccine targets ranging from bacterial and viral pathogens to cancer and addiction.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtF2ktLfK&md5=e2b314a29050e3a7f370dcf0137aa250
    38. 38
      Gutjahr, A.; Papagno, L.; Nicoli, F.; Kanuma, T.; Kuse, N.; Cabral-Piccin, M. P.; Rochereau, N.; Gostick, E.; Lioux, T.; Perouzel, E. The STING Ligand cGamp Potentiates the Efficacy of Vaccine-Induced CD8+ T Cells. JCI Insight 2019, 4 (7), e125107,  DOI: 10.1172/jci.insight.125107
      There is no corresponding record for this reference.
    39. 39
      He, Y.; Hong, C.; Fletcher, S. J.; Berger, A. G.; Sun, X.; Yang, M.; Huang, S.; Belcher, A. M.; Irvine, D. J.; Li, J.; Hammond, P. T. Peptide-Based Cancer Vaccine Delivery Via the STINGΔTM-cGamp Complex. Adv. Healthc Mater. 2022, 11, e2200905  DOI: 10.1002/adhm.202200905
      39
      Peptide-Based Cancer Vaccine Delivery via the STINGΔTM-cGAMP Complex
      He, Yanpu; Hong, Celestine; Fletcher, Samantha J.; Berger, Adam G.; Sun, Xin; Yang, Mengdi; Huang, Shengnan; Belcher, Angela M.; Irvine, Darrell J.; Li, Jiahe; Hammond, Paula T.
      Advanced Healthcare Materials (2022), 11 (15), 2200905CODEN: AHMDBJ; ISSN:2192-2640. (Wiley-VCH Verlag GmbH & Co. KGaA)
      With the advent of bioinformatic tools in efficiently predicting neo-antigens, peptide vaccines have gained tremendous attention in cancer immunotherapy. However, the delivery of peptide vaccines remains a major challenge, primarily due to ineffective transport to lymph nodes and low immunogenicity. Here, a strategy for peptide vaccine delivery is reported by first fusing the peptide to the cytosolic domain of the stimulator of interferon genes protein (STINGΔTM), then complexing the peptide-STINGΔTM protein with STING agonist 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The process results in the formation of self-assembled cGAMP-peptide-STINGΔTM tetramers, which enables efficient lymphatic trafficking of the peptide. Moreover, the cGAMP-STINGΔTM complex acts not only as a protein carrier for the peptide, but also as a potent adjuvant capable of triggering STING signaling independent of endogenous STING protein-an esp. important attribute considering that certain cancer cells epigenetically silence their endogenous STING expression. With model antigen SIINFEKL, it is demonstrated that the platform elicits effective STING signaling in vitro, draining lymph node targeting in vivo, effective T cell priming in vivo as well as antitumoral immune response in a mouse colon carcinoma model, providing a versatile soln. to the challenges faced in peptide vaccine delivery.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhsFGqt7jK&md5=48caf8a595d73d5693dcfc610067baf7
    40. 40
      Li, X. D.; Wu, J.; Gao, D.; Wang, H.; Sun, L.; Chen, Z. J. Pivotal Roles of cGAS-cGAMP Signaling in Antiviral Defense and Immune Adjuvant Effects. Science 2013, 341, 1390– 1394,  DOI: 10.1126/science.1244040
      40
      Pivotal Roles of cGAS-cGAMP Signaling in Antiviral Defense and Immune Adjuvant Effects
      Li, Xiao-Dong; Wu, Jiaxi; Gao, Daxing; Wang, Hua; Sun, Lijun; Chen, Zhijian J.
      Science (Washington, DC, United States) (2013), 341 (6152), 1390-1394CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Invasion of microbial DNA into the cytoplasm of animal cells triggers a cascade of host immune reactions that help clear the infection; however, self DNA in the cytoplasm can cause autoimmune diseases. Biochem. approaches led to the identification of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) as a cytosolic DNA sensor that triggers innate immune responses. Here, we show that cells from cGAS-deficient (cGas-/-) mice, including fibroblasts, macrophages, and dendritic cells, failed to produce type I interferons and other cytokines in response to DNA transfection or DNA virus infection. cGas-/- mice were more susceptible to lethal infection with herpes simplex virus 1 (HSV1) than wild-type mice. We also show that cGAMP is an adjuvant that boosts antigen-specific T cell activation and antibody prodn. in mice.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVCmu7vK&md5=46c48534439d7b6442911d63f7c3fa51
    41. 41
      Van Herck, S.; Feng, B.; Tang, L. Delivery of STING Agonists for Adjuvanting Subunit Vaccines. Adv. Drug Deliv Rev. 2021, 179, 114020,  DOI: 10.1016/j.addr.2021.114020
      41
      Delivery of STING agonists for adjuvanting subunit vaccines
      Van Herck, Simon; Feng, Bing; Tang, Li
      Advanced Drug Delivery Reviews (2021), 179 (), 114020CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
      A review. Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the immunogenicity and efficacy of vaccines. Recently discovered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has attracted much attention as it is a key mediator for modulating immune responses. Vaccines adjuvanted with STING agonists are found to mediate a robust immune defense against infections and cancer. In this review, we first discuss the mechanisms of STING agonists in the context of vaccination. Next, we present recent progress in novel STING agonist discovery and the delivery strategies. We next highlight recent work in optimizing the efficacy while minimizing toxicity of STING agonist-assisted subunit vaccines for protection against infectious diseases or treatment of cancer. Finally, we share our perspectives of current issues and future directions in further developing STING agonists for adjuvanting subunit vaccines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXisVyrsrnM&md5=991bac587ff443dcb8ebbbdef18d31ae
    42. 42
      Embgenbroich, M.; Burgdorf, S. Current Concepts of Antigen Cross-Presentation. Front Immunol 2018, 9, 1643,  DOI: 10.3389/fimmu.2018.01643
      42
      Current concepts of antigen cross-presentation
      Embgenbroich, Maria; Burgdorf, Sven
      Frontiers in Immunology (2018), 9 (), 1643/1-1643/10CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
      Dendritic cells have the ability to efficiently present internalized antigens on major histocompatibility complex (MHC) I mols. This process is termed cross-presentation and is important role in the generation of an immune response against viruses and tumors, after vaccinations or in the induction of immune tolerance. The mol. mechanisms enabling cross-presentation have been topic of intense debate since many years. However, a clear view on these mechanisms remains difficult, partially due to important remaining questions, controversial results and discussions. Here, we give an overview of the current concepts of antigen cross-presentation and focus on a description of the major cross-presentation pathways, the role of retarded antigen degrdn. for efficient cross-presentation, the dislocation of antigens from endosomal compartment into the cytosol, the reverse transport of proteasome-derived peptides for loading on MHC I and the translocation of the cross-presentation machinery from the ER to endosomes. We try to highlight recent advances, discuss some of the controversial data and point out some of the major open questions in the field.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitlSisLvP&md5=c6d5b139383717e9d5ed31dafc8a55d3
    43. 43
      Tom, J. K.; Albin, T. J.; Manna, S.; Moser, B. A.; Steinhardt, R. C.; Esser-Kahn, A. P. Applications of Immunomodulatory Immune Synergies to Adjuvant Discovery and Vaccine Development. Trends Biotechnol 2019, 37, 373– 388,  DOI: 10.1016/j.tibtech.2018.10.004
      43
      Applications of Immunomodulatory Immune Synergies to Adjuvant Discovery and Vaccine Development
      Tom, Janine K.; Albin, Tyler J.; Manna, Saikat; Moser, Brittany A.; Steinhardt, Rachel C.; Esser-Kahn, Aaron P.
      Trends in Biotechnology (2019), 37 (4), 373-388CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
      A review. Pathogens comprise a diverse set of immunostimulatory mols. that activate the innate immune system during infection. The immune system recognizes distinct combinations of pathogenic mols. leading to multiple immune activation events that cooperate to produce enhanced immune responses, known as 'immune synergies'. Effective immune synergies are essential for the clearance of pathogens, thus inspiring novel adjuvant design to improve vaccines. We highlight current vaccine adjuvants and the importance of immune synergies to adjuvant and vaccine design. The focus is on new technologies used to study and apply immune synergies to adjuvant and vaccine development. Finally, we discuss how recent findings can be applied to the future design and characterization of synergistic adjuvants and vaccines.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitV2itbrN&md5=c5510e87652758ab52910904679d93f2
    44. 44
      Collier, M. A.; Junkins, R. D.; Gallovic, M. D.; Johnson, B. M.; Johnson, M. M.; Macintyre, A. N.; Sempowski, G. D.; Bachelder, E. M.; Ting, J. P.; Ainslie, K. M. Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists. Mol. Pharmaceutics 2018, 15, 4933– 4946,  DOI: 10.1021/acs.molpharmaceut.8b00579
      44
      Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists
      Collier, Michael A.; Junkins, Robert D.; Gallovic, Matthew D.; Johnson, Brandon M.; Johnson, Monica M.; Macintyre, Andrew N.; Sempowski, Gregory D.; Bachelder, Eric M.; Ting, Jenny P.-Y.; Ainslie, Kristy M.
      Molecular Pharmaceutics (2018), 15 (11), 4933-4946CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
      Vaccines are the most effective tool for preventing infectious diseases; however, subunit vaccines, considered the safest type, suffer from poor immunogenicity and require adjuvants to create a strong and sustained immune response. As adjuvants, pathogen-assocd. mol. patterns (PAMPs) offer potent immunostimulatory properties and defined mechanisms of action through their cognate pattern recognition receptors (PRRs). Their activity can be further enhanced through combining two or more PAMPs, particularly those that activate multiple immune signaling pathways. However, the cytosolic localization of many PRRs requires intracellular delivery of PAMPs for optimal biol. activity, which is particularly true of the stimulator of interferon genes (STING) PRR. Using acetalated dextran (Ace-DEX) microparticles (MPs) encapsulating STING agonist 3'3'-cyclic GMP-AMP (cGAMP) combined with sol. PAMPS, we screened the effect of codelivery of adjuvants using primary mouse bone marrow derived dendritic cells (BMDCs). We identified that codelivery of cGAMP MPs and sol. Toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) elicited the broadest cytokine response. CGAMP and R848 were then coencapsulated within Ace-DEX MPs via electrospray. Using the model antigen ovalbumin, we obsd. that Ace-DEX MPs coencapsulating cGAMP and R848 (cGAMP/R848 Ace-DEX MPs) induced antigen-specific cellular immunity, and a balanced Th1/Th2 humoral response that was greater than cGAMP Ace-DEX MPs alone and PAMPs delivered in sep. MPs. These data indicate that polymeric Ace-DEX MPs loaded with STING and TLR7/8 agonists represent a potent cellular and humoral vaccine adjuvant.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvVertLvM&md5=72cfae51f29f59ae7c4a6b11a36d7acb
    45. 45
      Barman, S.; Borriello, F.; Brook, B.; Pietrasanta, C.; De Leon, M.; Sweitzer, C.; Menon, M.; van Haren, S. D.; Soni, D.; Saito, Y.; Nanishi, E.; Yi, S.; Bobbala, S.; Levy, O.; Scott, E. A.; Dowling, D. J. Shaping Neonatal Immunization by Tuning the Delivery of Synergistic Adjuvants Via Nanocarriers. ACS Chem. Biol. 2022, 17, 2559– 2571,  DOI: 10.1021/acschembio.2c00497
      45
      Shaping Neonatal Immunization by Tuning the Delivery of Synergistic Adjuvants via Nanocarriers
      Barman, Soumik; Borriello, Francesco; Brook, Byron; Pietrasanta, Carlo; De Leon, Maria; Sweitzer, Cali; Menon, Manisha; van Haren, Simon D.; Soni, Dheeraj; Saito, Yoshine; Nanishi, Etsuro; Yi, Sijia; Bobbala, Sharan; Levy, Ofer; Scott, Evan A.; Dowling, David J.
      ACS Chemical Biology (2022), 17 (9), 2559-2571CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
      Adjuvanted nanocarrier-based vaccines hold substantial potential for applications in novel early-life immunization strategies. Here, via mouse and human age-specific in vitro modeling, we identified the combination of a small-mol. STING agonist (2'3'-cyclic GMP-AMP, cGAMP) and a TLR7/8 agonist (CL075) to drive the synergistic activation of neonatal dendritic cells and precision CD4 T-helper (Th) cell expansion via the IL-12/IFNγ axis. We further demonstrate that the vaccination of neonatal mice with quadrivalent influenza recombinant hemagglutinin (rHA) and an admixt. of two polymersome (PS) nanocarriers sep. encapsulating cGAMP (cGAMP-PS) and CL075 (CL075-PS) drove robust Th1 bias, high frequency of T follicular helper (TFH) cells, and germinal center (GC) B cells along with the IgG2c-skewed humoral response in vivo. Dual-loaded cGAMP/CL075-PSs did not outperform admixed cGAMP-PS and CL075-PS in vivo. These data validate an optimally designed adjuvantation system via age-selected small-mol. synergy and a multicomponent nanocarrier formulation as an effective approach to induce type 1 immune responses in early life.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38Xit1alsb3K&md5=779648f1160a984f3c8b7b98026bf77c
    46. 46
      Kuai, R.; Sun, X.; Yuan, W.; Ochyl, L. J.; Xu, Y.; Hassani Najafabadi, A.; Scheetz, L.; Yu, M. Z.; Balwani, I.; Schwendeman, A.; Moon, J. J. Dual TLR Agonist Nanodiscs as a Strong Adjuvant System for Vaccines and Immunotherapy. J. Controlled Release 2018, 282, 131– 139,  DOI: 10.1016/j.jconrel.2018.04.041
      46
      Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy
      Kuai, Rui; Sun, Xiaoqi; Yuan, Wenmin; Ochyl, Lukasz J.; Xu, Yao; Hassani Najafabadi, Alireza; Scheetz, Lindsay; Yu, Min-Zhi; Balwani, Ishina; Schwendeman, Anna; Moon, James J.
      Journal of Controlled Release (2018), 282 (), 131-139CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      Recent studies have shown that certain combinations of Toll-like receptor (TLR) agonists can induce synergistic immune activation. However, it remains challenging to achieve such robust responses in vivo in a manner that is effective, facile, and amenable for clin. translation. Here, we show that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-d. lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides. ND-MPLA/CpG significantly enhanced activation of dendritic cells, compared with free dual adjuvants or nanodiscs delivering a single TLR agonist. Importantly, mice immunized with phys. mixts. of protein antigens ND-MPLA/CpG generated strong humoral responses, including induction of IgG responses against protein convertase subtilisin/kexin 9 (PCSK9), leading to 17-30% redn. of the total plasma cholesterol levels. Moreover, ND-MPLA/CpG exerted strong anti-tumor efficacy in multiple murine tumor models. Compared with free adjuvants, ND-MPLA/CpG admixed with ovalbumin markedly improved antigen-specific CD8+ T cell responses by 8-fold and promoted regression of B16F10-OVA melanoma (P<0.0001). Furthermore, ND-MPLA/CpG admixed with E7 peptide antigen elicited ∼20% E7-specific CD8+ T cell responses and achieved complete regression of established TC-1 tumors in all treated animals. Taken together, our work highlights the simplicity, versatility, and potency of dual TLR agonist nanodiscs for applications in vaccines and cancer immunotherapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXosFWrtr0%253D&md5=00b84399e940517a6e19c016bd9fc318
    47. 47
      Zhang, B. D.; Wu, J. J.; Li, W. H.; Hu, H. G.; Zhao, L.; He, P. Y.; Zhao, Y. F.; Li, Y. M. STING and TLR7/8 Agonists-Based Nanovaccines for Synergistic Antitumor Immune Activation. Nano Res. 2022, 15, 6328– 6339,  DOI: 10.1007/s12274-022-4282-x
      47
      STING and TLR7/8 agonists-based nanovaccines for synergistic antitumor immune activation
      Zhang, Bo-Dou; Wu, Jun-Jun; Li, Wen-Hao; Hu, Hong-Guo; Zhao, Lang; He, Pei-Yang; Zhao, Yu-Fen; Li, Yan-Mei
      Nano Research (2022), 15 (7), 6328-6339CODEN: NRAEB5; ISSN:1998-0000. (Springer GmbH)
      Immunostimulatory therapies based on pattern recognition receptors (PRRs) have emerged as an effective approach in the fight against cancer, with the ability to recruit tumor-specific lymphocytes in a low-immunogenicity tumor environment. The agonist cyclic dinucleotides (CDNs) of the stimulator of interferon gene (STING) are a group of very promising anticancer mols. that increase tumor immunogenicity by activating innate immunity. However, the tumor immune efficacy of CDNs is limited by several factors, including relatively narrow cytokine prodn., inefficient delivery to STING, and rapid clearance. In addn., a single adjuvant mol. is unable to elicit a broad cytokine response and thus cannot further amplify the anticancer effect. To address this problem, two or more agonist mols. are often used together to synergistically enhance immune efficacy. In this work, we found that a combination of the STING agonist CDGSF and the Toll-like receptor 7/8 (TLR7/8) agonist 522 produced a broader cytokine response. Subsequently, we developed multicomponent nanovaccines (MCNVs) consisting of a PC7A polymer as a nanocarrier encapsulating the antigen OVA and adjuvant mols. These MCNVs activate bone marrow-derived dendritic cells (BMDCs) to produce multiple proinflammatory factors that promote antigen cross-presentation to stimulate specific antitumor T-cell responses. In in vivo expts., we obsd. that MCNVs triggered a strong T-cell response in tumor-infiltrating lymphocytes, resulting in significant tumor regression and, notably, a 100% survival rate in mice through 25 days without other partnering therapies. These data suggest that our nanovaccines have great potential to advance cancer immunotherapy with increased durability and potency.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XhtVeitLbO&md5=0103b8d2efebe7669675a9d6ee1e51b5
    48. 48
      Pradhan, P.; Toy, R.; Jhita, N.; Atalis, A.; Pandey, B.; Beach, A.; Blanchard, E. L.; Moore, S. G.; Gaul, D. A.; Santangelo, P. J. TRAF6-IRF5 Kinetics, TRIF, and Biophysical Factors Drive Synergistic Innate Responses to Particle-Mediated MPLA-CpG Co-Presentation. Sci. Adv. 2021, 7, abd4235,  DOI: 10.1126/sciadv.abd4235
      There is no corresponding record for this reference.
    49. 49
      Temizoz, B.; Kuroda, E.; Ohata, K.; Jounai, N.; Ozasa, K.; Kobiyama, K.; Aoshi, T.; Ishii, K. J. TLR9 and STING Agonists Synergistically Induce Innate and Adaptive Type-II IFN. Eur. J. Immunol. 2015, 45, 1159– 1169,  DOI: 10.1002/eji.201445132
      49
      TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN
      Temizoz, Burcu; Kuroda, Etsushi; Ohata, Keiichi; Jounai, Nao; Ozasa, Koji; Kobiyama, Kouji; Aoshi, Taiki; Ishii, Ken J.
      European Journal of Immunology (2015), 45 (4), 1159-1169CODEN: EJIMAF; ISSN:0014-2980. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Agonists for TLR9 and Stimulator of IFN Gene (STING) act as vaccine adjuvants that induce type-1 immune responses. However, currently available CpG oligodeoxynucleotide (ODN) (K-type) induces IFNs only weakly and STING ligands rather induce type-2 immune responses, limiting their potential therapeutic applications. Here, we show a potent synergism between TLR9 and STING agonists. Together, they make an effective type-1 adjuvant and an anticancer agent. The synergistic effect between CpG ODN (K3) and STING-ligand cyclic GMP-AMP (cGAMP), culminating in NK cell IFN-γ (type-II IFN) prodn., is due to the concurrent effects of IL-12 and type-I IFNs, which are differentially regulated by IRF3/7, STING, and MyD88. The combination of CpG ODN with cGAMP is a potent type-1 adjuvant, capable of inducing strong Th1-type responses, as demonstrated by enhanced antigen-specific IgG2c and IFN-γ prodn., as well as cytotoxic CD8+ T-cell responses. In our murine tumor models, intratumoral injection of CpG ODN and cGAMP together reduced tumor size significantly compared with the singular treatments, acting as an antigen-free anticancer agent. Thus, the combination of CpG ODN and a STING ligand may offer therapeutic application as a potent type-II IFN inducer.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXks12gsr4%253D&md5=01e7129b3bc00d09165a64e1fa103859
    50. 50
      Kim, J. Y.; Rosenberger, M. G.; Chen, S.; Ip, C. K.; Bahmani, A.; Chen, Q.; Shen, J.; Tang, Y.; Wang, A.; Kenna, E.; Son, M.; Tay, S.; Ferguson, A. L.; Esser-Kahn, A. P. Discovery of New States of Immunomodulation for Vaccine Adjuvants Via High Throughput Screening: Expanding Innate Responses to PRRs. ACS Cent Sci. 2023, 9, 427– 439,  DOI: 10.1021/acscentsci.2c01351
      50
      Discovery of New States of Immunomodulation for Vaccine Adjuvants via High Throughput Screening: Expanding Innate Responses to PRRs
      Kim, Jeremiah Y.; Rosenberger, Matthew G.; Chen, Siquan; IP, Carman KM; Bahmani, Azadeh; Chen, Qing; Shen, Jinjing; Tang, Yifeng; Wang, Andrew; Kenna, Emma; Son, Minjun; Tay, Savas; Ferguson, Andrew L.; Esser-Kahn, Aaron P.
      ACS Central Science (2023), 9 (3), 427-439CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)
      Stimulation of the innate immune system is crucial in both effective vaccinations and immunotherapies. This is often achieved through adjuvants, mols. that usually activate pattern recognition receptors (PRRs) and stimulate two innate immune signaling pathways: the nuclear factor kappa-light-chain-enhancer of activated B-cells pathway (NF-κB) and the interferon regulatory factors pathway (IRF). Here, we demonstrate the ability to alter and improve adjuvant activity via the addn. of small mol. "immunomodulators". By modulating signaling activity instead of receptor binding, these mols. allow the customization of select innate responses. We demonstrate both inhibition and enhancement of the products of the NF-κB and IRF pathways by several orders of magnitude. Some modulators apply generally across many receptors, while others focus specifically on individual receptors. Modulators boost correlates of a protective immune responses in a com. flu vaccine model and reduced correlates of reactogenicity in a typhoid vaccine model. These modulators have a range of applications: from adjuvanticity in prophylactics to enhancement of immunotherapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXjs1ygtb4%253D&md5=b2ef1701e544feba43084f5fc8b5d3ad
    51. 51
      Nihesh, N.; Manna, S.; Studnitzer, B.; Shen, J.; Esser-Kahn, A. P. A Synthetic Pathogen Mimetic Molecule Induces a Highly Amplified Synergistic Immune Response Via Activation of Multiple Signaling Pathways. Chem. Sci. 2021, 12, 6646– 6651,  DOI: 10.1039/D1SC00964H
      51
      A synthetic pathogen mimetic molecule induces a highly amplified synergistic immune response via activation of multiple signaling pathways
      Nihesh, Naorem; Manna, Saikat; Studnitzer, Bradley; Shen, Jingjing; Esser-Kahn, Aaron P.
      Chemical Science (2021), 12 (19), 6646-6651CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      The current understanding of how the immune system processes complex information during natural infections is yet to be exploited for the mol. design of potent immune activators. Here, we address this challenge by design of a pathogen-mimetic mol. that simultaneously co-activates cell-surface active, endosomal and cytosolic immune receptors.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXnvVGitr8%253D&md5=26cbbad0fab4671e7767affb9acdd81a
    52. 52
      Taylor, D.; Meyer, C. T.; Graves, D.; Sen, R.; Fu, J.; Tran, E.; Mirza, B.; Rodriguez, G.; Lang, C.; Feng, H.; Quaranta, V.; Wilson, J. T.; Kim, Y. J.; Korrer, M. J. MuSyC Dosing of Adjuvanted Cancer Vaccines Optimizes Antitumor Responses. Front Immunol 2022, 13, 936129,  DOI: 10.3389/fimmu.2022.936129
      52
      MuSyC dosing of adjuvanted cancer vaccines optimizes antitumor responses
      Taylor, David; Meyer, Christian T.; Graves, Diana; Sen, Rupashree; Fu, Juan; Tran, Emily; Mirza, Bilal; Rodriguez, Gabriel; Lang, Cara; Feng, Hanwen; Quaranta, Vito; Wilson, John T.; Kim, Young J.; Korrer, Michael J.
      Frontiers in Immunology (2022), 13 (), 936129CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
      With the clin. approval of T-cell-dependent immune checkpoint inhibitors for many cancers, therapeutic cancer vaccines have re-emerged as a promising immunotherapy. Cancer vaccines require the addn. of immunostimulatory adjuvants to increase vaccine immunogenicity, and increasingly multiple adjuvants are used in combination to bolster further and shape cellular immunity to tumor antigens. However, rigorous quantification of adjuvants' synergistic interactions is challenging due to partial redundancy in costimulatory mols. and cytokine prodn., leading to the common assumption that combining both adjuvants at the max. tolerated dose results in optimal efficacy. Herein, we examine this max. dose assumption and find combinations of these doses are suboptimal. Instead, we optimized dendritic cell activation by extending the Multidimensional Synergy of Combinations (MuSyC) framework that measures the synergy of efficacy and potency between two vaccine adjuvants. Initially, we performed a preliminary in vitro screening of clin. translatable adjuvant receptor targets (TLR, STING, NLL, and RIG-I). We detd. that STING agonist (CDN) plus TLR4 agonist (MPL-A) or TLR7/8 agonist (R848) as the best pairwise combinations for dendritic cell activation. In addn., we found that the combination of R848 and CDN is synergistically efficacious and potent in activating both murine and human antigen-presenting cells (APCs) in vitro. These two selected adjuvants were then used to est. a MuSyC-dose optimized for in vivo T-cell priming using ovalbumin-based peptide vaccines. Finally, using B16 melanoma and MOC1 head and neck cancer models, MuSyC-dose-based adjuvating of cancer vaccines improved the antitumor response, increased tumor infiltrating lymphocytes, and induced novel myeloid tumor infiltration changes. Further, the MuSyC-dose-based adjuvants approach did not cause addnl. wt. changes or increased plasma cytokine levels compared to CDN alone. Collectively, our findings offer a proof of principle that our MuSyC-extended approach can be used to optimize cancer vaccine formulations for immunotherapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XitlChu73M&md5=4f4dfbaf0362bfb299001faff278e0f6
    53. 53
      Hanson, M. C.; Crespo, M. P.; Abraham, W.; Moynihan, K. D.; Szeto, G. L.; Chen, S. H.; Melo, M. B.; Mueller, S.; Irvine, D. J. Nanoparticulate STING Agonists Are Potent Lymph Node-Targeted Vaccine Adjuvants. J. Clin Invest 2015, 125, 2532– 2546,  DOI: 10.1172/JCI79915
      53
      Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants
      Hanson Melissa C; Crespo Monica P; Abraham Wuhbet; Moynihan Kelly D; Szeto Gregory L; Chen Stephanie H; Melo Mariane B; Mueller Stefanie; Irvine Darrell J
      The Journal of clinical investigation (2015), 125 (6), 2532-46 ISSN:.
      Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MfgsVChtw%253D%253D&md5=b840cee3cc090db0b723072b6936b05c
    54. 54
      Atukorale, P. U.; Raghunathan, S. P.; Raguveer, V.; Moon, T. J.; Zheng, C.; Bielecki, P. A.; Wiese, M. L.; Goldberg, A. L.; Covarrubias, G.; Hoimes, C. J.; Karathanasis, E. Nanoparticle Encapsulation of Synergistic Immune Agonists Enables Systemic Codelivery to Tumor Sites and IFNβ-Driven Antitumor Immunity. Cancer Res. 2019, 79, 5394– 5406,  DOI: 10.1158/0008-5472.CAN-19-0381
      54
      Nanoparticle encapsulation of synergistic immune agonists enables systemic codelivery to tumor sites and IFNβ-driven antitumor immunity
      Atukorale, Prabhani U.; Raghunathan, Shruti P.; Raguveer, Vanitha; Moon, Tayior J.; Zheng, Carolyn; Bielecki, Peter A.; Wiese, Michelle L.; Goldberg, Amy L.; Covarrubias, Gil; Hoimes, Christopher J.; Karathanasis, Efstathios
      Cancer Research (2019), 79 (20), 5394-5406CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
      Effective cancer immunotherapy depends on the robust activation of tumor-specific antigen-presenting cells (APC). Immune agonists encapsulated within nanoparticles (NP) can be delivered to tumor sites to generate powerful antitumor immune responses with minimal off-target dissemination. Systemic delivery enables widespread access to the microvasculature and draining to the APC-rich perivasculature. We developed an immuno-nanoparticle (immuno-NP) coloaded with cyclic diguanylate monophosphate, an agonist of the stimulator of interferon genes pathway, and monophosphoryl lipid A, and a Toll-like receptor 4 agonist, which synergize to produce high levels of type I ΙΡΝβ. Usinga murine model of metastatic triple-neg. breast cancer. systemic delivery of these immuno-NPs resulted in significant therapeutic outcomes due to extensive upregulation of APCs and natural killer cells in the blood and tumor compared with control treatments. These results indicate that NPs can facilitate systemic delivery of multiple immune potentiating cargoes for effective APC-driven local and systemic antitumor immunity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFSqtb0%253D&md5=469de56cb58341e82e13aa77c48c6515
    55. 55
      Pandey, S.; Gruenbaum, A.; Kanashova, T.; Mertins, P.; Cluzel, P.; Chevrier, N. Pairwise Stimulations of Pathogen-Sensing Pathways Predict Immune Responses to Multi-Adjuvant Combinations. Cell Syst 2020, 11, 495– 508,  DOI: 10.1016/j.cels.2020.10.001
      55
      Pairwise Stimulations of Pathogen-Sensing Pathways Predict Immune Responses to Multi-adjuvant Combinations
      Pandey, Surya; Gruenbaum, Adam; Kanashova, Tamara; Mertins, Philipp; Cluzel, Philippe; Chevrier, Nicolas
      Cell Systems (2020), 11 (5), 495-508.e10CODEN: CSEYA4; ISSN:2405-4712. (Cell Press)
      The immune system makes decisions in response to combinations of multiple microbial inputs. We do not understand the combinatorial logic governing how higher-order combinations of microbial signals shape immune responses. Here, using coculture expts. and statistical analyses, we discover a general property for the combinatorial sensing of microbial signals, whereby the effects of triplet combinations of microbial signals on immune responses can be predicted by combining the effects of single and pairs. Mechanistically, we find that singles and pairs dictate the information signaled by triplets in mouse and human DCs at the levels of transcription, chromatin, and protein secretion. We exploit this simplifying property to develop cell-based immunotherapies prepd. with adjuvant combinations that trigger protective responses in mouse models of cancer. We conclude that the processing of multiple input signals by innate immune cells is governed by pairwise effects, which will inform the rationale combination of adjuvants to manipulate immunity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXisVaqu7jK&md5=04738bf46febbbc04848669c0147be24
    56. 56
      Andrade, W. A.; Agarwal, S.; Mo, S.; Shaffer, S. A.; Dillard, J. P.; Schmidt, T.; Hornung, V.; Fitzgerald, K. A.; Kurt-Jones, E. A.; Golenbock, D. T. Type I Interferon Induction by Neisseria Gonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-Like Receptor 4. Cell Rep 2016, 15, 2438– 2448,  DOI: 10.1016/j.celrep.2016.05.030
      56
      Type I Interferon Induction by Neisseriagonorrhoeae: Dual Requirement of Cyclic GMP-AMP Synthase and Toll-like Receptor 4
      Andrade, Warrison A.; Agarwal, Sarika; Mo, Shunyan; Shaffer, Scott A.; Dillard, Joseph P.; Schmidt, Tobias; Hornung, Veit; Fitzgerald, Katherine A.; Kurt-Jones, Evelyn A.; Golenbock, Douglas T.
      Cell Reports (2016), 15 (11), 2438-2448CODEN: CREED8; ISSN:2211-1247. (Cell Press)
      The innate immune system is the first line of defense against Neisseria gonorrhoeae (GC). Exposure of cells to GC lipooligosaccharides induces a strong immune response, leading to type I interferon (IFN) prodn. via TLR4/MD-2. In addn. to living freely in the extracellular space, GC can invade the cytoplasm to evade detection and elimination. Double-stranded DNA introduced into the cytosol binds and activates the enzyme cyclic-GMP-AMP synthase (cGAS), which produces 2'3'-cGAMP and triggers STING/TBK-1/IRF3 activation, resulting in type I IFN expression. Here, we reveal a cytosolic response to GC DNA that also contributes to type I IFN induction. We demonstrate that complete IFN-β induction by live GC depends on both cGAS and TLR4. Type I IFN is detrimental to the host, and dysregulation of iron homeostasis genes may explain lower bacteria survival in cGAS-/- and TLR4-/- cells. Collectively, these observations reveal cooperation between TLRs and cGAS in immunity to GC infection.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xpt1entbg%253D&md5=55421b21e0d3fce79cfbfe853151908d
    57. 57
      Kocabas, B. B.; Almacioglu, K.; Bulut, E. A.; Gucluler, G.; Tincer, G.; Bayik, D.; Gursel, M.; Gursel, I. Dual-Adjuvant Effect of pH-Sensitive Liposomes Loaded with STING and TLR9 Agonists Regress Tumor Development by Enhancing Th1 Immune Response. J. Controlled Release 2020, 328, 587– 595,  DOI: 10.1016/j.jconrel.2020.09.040
      57
      Dual-adjuvant effect of pH-sensitive liposomes loaded with STING and TLR9 agonists regress tumor development by enhancing Th1 immune response
      Kocabas, Banu Bayyurt; Almacioglu, Kubra; Bulut, Esin Alpdundar; Gucluler, Gozde; Tincer, Gizem; Bayik, Defne; Gursel, Mayda; Gursel, Ihsan
      Journal of Controlled Release (2020), 328 (), 587-595CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      Nucleic acid-based pattern recognition receptor agonists are effective adjuvants and immunotherapeutic agents. Rather than single applications, ligand combinations could synergistically potentiate immune responses by elevating cytokine and chemokine prodn. via triggering multiple signaling pathways. However, short half-lives of such labile ligands due to nuclease attack and limited cellular uptake due to their structure significantly hamper their in vivo performances. More importantly, simultaneous delivery and activity presentation of protein antigen and nucleic acid ligands critically limit the clin. development of these constructs. In this work, we approached this problem by co-encapsulating a model antigen ovalbumin along with TLR9 and STING ligands within liposomes, a well-established drug delivery system that enables payload stability and enhanced cellular activity upon internalization. Moreover, by loading dual ligands we postulated to achieve heightened Th-1 immune response that would yield pronounced protective vaccine efficacy. We show that, pH-sensitive liposomes co-encapsulating CpG ODN and cGAMP induced synergistic innate immune response by elevating type I and type II interferon levels. Most importantly, this vaccine formulation led to ∼70% regression of established melanoma tumor. pH-sensitive liposomal vaccine administration elevated IgG2c/IgG1 antibody ratio, indicative of augmented OVA-specific Th1-biased immunity. Importantly, while the frequency of tumor-specific IFN-γ producing CD8+ T-cells was significantly increased, the M2-type anti-inflammatory macrophage levels were decreased in the tumor bed. In conclusion, our strategy induces reversal of immunosuppressive tumor microenvironment, while enhancing effective anti-tumor immune-response. We propose that this could be coupled with std. therapies during combating tumor eradication.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVCks7bE&md5=2eb22cda1e9a367c6e5e6757380a13ef
    58. 58
      Toy, R.; Keenum, M. C.; Pradhan, P.; Phang, K.; Chen, P.; Chukwu, C.; Nguyen, L. A. H.; Liu, J.; Jain, S.; Kozlowski, G.; Hosten, J.; Suthar, M. S.; Roy, K. TLR7 and RIG-I Dual-Adjuvant Loaded Nanoparticles Drive Broadened and Synergistic Responses in Dendritic Cells in Vitro and Generate Unique Cellular Immune Responses in Influenza Vaccination. J. Controlled Release 2021, 330, 866– 877,  DOI: 10.1016/j.jconrel.2020.10.060
      58
      TLR7 and RIG-I dual-adjuvant loaded nanoparticles drive broadened and synergistic responses in dendritic cells in vitro and generate unique cellular immune responses in influenza vaccination
      Toy, Randall; Keenum, M. Cole; Pradhan, Pallab; Phang, Katelynn; Chen, Patrick; Chukwu, Chinwendu; Nguyen, Lily Anh H.; Liu, Jiaying; Jain, Sambhav; Kozlowski, Gabrielle; Hosten, Justin; Suthar, Mehul S.; Roy, Krishnendu
      Journal of Controlled Release (2021), 330 (), 866-877CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      Although the existing flu vaccines elicit strong antigen-specific antibody responses, they fail to provide effective, long term protection - partly due to the absence of robust cellular memory immunity. We hypothesized that co-administration of combination adjuvants, mirroring the flu-virus related innate signaling pathways, could elicit strong cellular immunity. Here, we show that the small mol. adjuvant R848 and the RNA adjuvant PUUC, targeting endosomal TLR7s and cytoplasmic RLRs resp., when delivered together in polymer nanoparticles (NP), elicits a broadened immune responses in mouse bone marrow-derived dendritic cells (mBMDCs) and a synergistic response in both mouse and human plasmacytoid dendritic cells (pDCs). In mBMDCs, NP-R848-PUUC induced both NF-κB and interferon signaling. Interferon responses to co-delivered R848 and PUUC were additive in human peripheral blood mononuclear cells (PBMCs) and synergistic in human FLT3-differentiated mBMDCs and CAL-1 pDCs. Vaccination with NPs loaded with H1N1 Flu antigen, R848, and PUUC increased percentage of CD8+ T-cells in the lungs, percentage of antigen-specific CD4-T-cells in the spleen, and enhanced overall cytokine-secreting T cell percentages upon antigen restimulation. Also, in the spleen, T lymphopenia, esp. after in vitro restimulation with dual adjuvants, was obsd., indicating highly antigen-reactive T cells. Our results demonstrate that simultaneous engagement of TLR7 and RIG-I pathways using particulate carriers is a potential approach to improve cellular immunity in flu vaccination.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitlCku7rE&md5=4985b3db7e0bf52f50272a1d4e1238dc
    59. 59
      Hou, Y.; Wang, Y.; Tang, Y.; Zhou, Z.; Tan, L.; Gong, T.; Zhang, L.; Sun, X. Co-Delivery of Antigen and Dual Adjuvants by Aluminum Hydroxide Nanoparticles for Enhanced Immune Responses. J. Controlled Release 2020, 326, 120– 130,  DOI: 10.1016/j.jconrel.2020.06.021
      59
      Co-delivery of antigen and dual adjuvants by aluminum hydroxide nanoparticles for enhanced immune responses
      Hou, Yingying; Wang, Ying; Tang, Yao; Zhou, Zixuan; Tan, Lu; Gong, Tao; Zhang, Ling; Sun, Xun
      Journal of Controlled Release (2020), 326 (), 120-130CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      Adjuvants that contain pathogen-assocd. mol. patterns (PAMPs) can enhance vaccination efficacy by binding to pattern recognition receptors (PRRs), thereby stimulating immune responses. Particularly effective may be the combination of multiple PAMPs that activate different PRRs, which occurs with natural pathogens. Here we hypothesized the enhanced effects would occur in two adjuvants that stimulate different PRRs: CpG oligodeoxynucleotide (CpG-ODN), which is Toll-like receptor 9 agonist; and 5'-triphosphate, short, double-stranded RNA (3pRNA), which activates retinoic acid-inducible gene I (RIG-I). The model antigen ovalbumin (OVA) was loaded and adjuvants were surface-adsorbed to aluminum hydroxide nanoparticles (hereafter NP-3pRNA-CpG) by electrostatic interaction with an av. size of 120 nm and a neg. surface charge for targeting lymph nodes. These nanoparticles were efficiently internalized by antigen-presenting cells (APCs) in the lymph nodes, and the resulting APC activation and antigen cross-presentation generated strong humoral immunity and cytotoxic T lymphocyte responses and IFN-γ secretion. NP-3pRNA-CpG significantly suppressed B16-OVA tumor growth and prolonged survival of tumor-bearing mice in therapeutic and prophylactic models, illustrating the enhanced effects of CpG-ODN and 3pRNA. Our study highlights the potential of combining multiple adjuvants for effective vaccine design.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXht1Kgu7bL&md5=ec7771ba4a626526fd70d75d7fa0af14
    60. 60
      Pagendarm, H. M.; Stone, P. T.; Kimmel, B. R.; Baljon, J. J.; Aziz, M. H.; Pastora, L. E.; Hubert, L.; Roth, E. W.; Almunif, S.; Scott, E. A.; Wilson, J. T. Engineering Endosomolytic Nanocarriers of Diverse Morphologies Using Confined Impingement Jet Mixing. Nanoscale 2023, 15, 16016– 16029,  DOI: 10.1039/D3NR02874G
      60
      Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing
      Pagendarm, Hayden M.; Stone, Payton T.; Kimmel, Blaise R.; Baljon, Jessalyn J.; Aziz, Mina H.; Pastora, Lucinda E.; Hubert, Lauren; Roth, Eric W.; Almunif, Sultan; Scott, Evan A.; Wilson, John T.
      Nanoscale (2023), 15 (39), 16016-16029CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
      The clin. translation of many biomol. therapeutics has been hindered by undesirable pharmacokinetic (PK) properties, inadequate membrane permeability, poor endosomal escape and cytosolic delivery, and/or susceptibility to degrdn. Overcoming these challenges merits the development of nanoscale drug carriers (nanocarriers) to improve the delivery of therapeutic cargo. Herein, we implement a flash nanopptn. (FNP) approach to produce nanocarriers of diverse vesicular morphologies by using various mol. wt. PEG-bl-DEAEMA-co-BMA (PEG-DB) polymers. We demonstrated that FNP can produce uniform (PDI < 0.1) particles after 5 impingements, and that by varying the copolymer hydrophilic mass fraction, FNP enables access to a diverse variety of nanoarchitectures including micelles, unilamellar vesicles (polymersomes), and multi-compartment vesicles (MCVs). We synthesized a library of 2 kDa PEG block copolymers, with DEAEMA-co-BMA second block mol. wts. of 3, 6, 12, 15, 20, and 30 kDa. All formulations were both pH responsive, endosomolytic, and capable of loading and cytosolically delivering small neg. charged mols. - albeit to different degrees. Using a B16. F10 melanoma model, we showcased the therapeutic potential of a lead FNP formulated PEG-DB nanocarrier, encapsulating the cyclic dinucleotide (CDN) cGAMP to activate the stimulator of interferon genes (STING) pathway in a therapeutically relevant context. Collectively, these data demonstrate that an FNP process can be used to formulate pH-responsive nanocarriers of diverse morphologies using a PEG-DB polymer system. As FNP is an industrially scalable process, these data address the crit. translational challenge of producing PEG-DB nanoparticles at scale. Furthermore, the diverse morphologies produced may specialize in the delivery of distinct biomol. cargos for other therapeutic applications, implicating the therapeutic potential of this platform in an array of disease applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXhvF2qsLnK&md5=04a78b16072f0ff7e9436c3c62991260
    61. 61
      Manganiello, M. J.; Cheng, C.; Convertine, A. J.; Bryers, J. D.; Stayton, P. S. Diblock Copolymers with Tunable pH Transitions for Gene Delivery. Biomaterials 2012, 33, 2301– 2309,  DOI: 10.1016/j.biomaterials.2011.11.019
      61
      Diblock copolymers with tunable pH transitions for gene delivery
      Manganiello, Matthew J.; Cheng, Connie; Convertine, Anthony J.; Bryers, James D.; Stayton, Patrick S.
      Biomaterials (2012), 33 (7), 2301-2309CODEN: BIMADU; ISSN:0142-9612. (Elsevier Ltd.)
      A series of diblock copolymers contg. an endosomal-releasing segment composed of diethylaminoethyl methacrylate (DEAEMA) and Bu methacrylate (BMA) were synthesized via reversible addn.-fragmentation chain transfer (RAFT) polymn. The materials were designed to condense plasmid DNA (pDNA) through electrostatic interactions with a cationic poly(N,N-dimethylaminoethyl methacrylate) (DMAEMA) first block. The pDMAEMA was employed as a macro chain transfer agent (macroCTA) for the synthesis of a series in which the relative feed ratios of DEAEMA and BMA were systematically varied from 20% to 70% BMA. The resultant diblock copolymers exhibited low polydispersity (PDI ≤ 1.06) with similar mol. wts. (Mn = 19.3-23.1 kDa). Dynamic light scattering (DLS) measurements in combination with 1H NMR D2O studies demonstrated that the free copolymers assemble into core-shell micelles at physiol. pH. Redn. of the soln. pH to values representative of endosomal/lysosomal compartments induced an increase in the net cationic charge of the core through protonation of the DEAEMA residues. This protonation promotes micelle destabilization and exposure of the hydrophobic BMA residues that destabilize biol. membranes. The pH value at which this micelle-to-unimer transition occurred was dependent on the hydrophobic content of the copolymer, with higher BMA-contg. copolymer compns. exhibiting pH-induced transitions to the membrane-destabilizing state at successively lower pH values. The ability of the diblock copolymers to deliver pDNA was subsequently investigated using a GFP expression vector in two monocyte cell lines. High levels of DNA transfection were obsd. for the copolymer compns. exhibiting the sharpest pH transitions and membrane destabilizing activities, demonstrating the importance of tuning the endosomal-releasing segment compn.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xnt1entw%253D%253D&md5=ec63b85f138fe9934ba5508bf04e594f
    62. 62
      Allen, S.; Osorio, O.; Liu, Y. G.; Scott, E. Facile Assembly and Loading of Theranostic Polymersomes Via Multi-Impingement Flash Nanoprecipitation. J. Controlled Release 2017, 262, 91– 103,  DOI: 10.1016/j.jconrel.2017.07.026
      62
      Facile assembly and loading of theranostic polymersomes via multi-impingement flash nanoprecipitation
      Allen, Sean; Osorio, Omar; Liu, Yu-Gang; Scott, Evan
      Journal of Controlled Release (2017), 262 (), 91-103CODEN: JCREEC; ISSN:0168-3659. (Elsevier B.V.)
      Flash nanopptn. has proven to be a powerful tool for the rapid and scalable assembly of solid-core nanoparticles from block copolymers. To date, FNP has not been applied for the fabrication of complex or vesicular nanoarchitectures capable of encapsulating hydrophilic mols. or bioactive protein therapeutics. Here, we present FNP as a single customizable method for the assembly of bicontinuous nanospheres, filomicelles and vesicular, multilamellar and tubular polymersomes from poly(ethylene glycol)-bl-poly(propylene sulfide) block copolymers. Multiple impingements of polymersomes assembled via FNP were shown to decrease vesicle diam. and polydispersity, allowing gram-scale fabrication of monodisperse polymersomes within minutes. Furthermore, we demonstrate that FNP supports simultaneous loading of both hydrophobic and hydrophilic mols. resp. into the polymersome membrane and aq. lumen, and encapsulated enzymes were found to be released and remain active following vesicle lysis. As an example application, theranostic polymersomes were generated via FNP that were dual loaded with the immunosuppressant rapamycin and a fluorescent dye to link targeted immune cells with the elicited immunomodulation of T cells. By expanding the capabilities of FNP, we present a rapid, scalable and reproducible method of nanofabrication for a wide range of nanoarchitectures that are typically challenging to assemble and load with therapeutics for controlled delivery and theranostic strategies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1egsbjK&md5=a52b3f1d74b3a23fe99693893e9eab06
    63. 63
      Han, J.; Zhu, Z.; Qian, H.; Wohl, A. R.; Beaman, C. J.; Hoye, T. R.; Macosko, C. W. A Simple Confined Impingement Jets Mixer for Flash Nanoprecipitation. J. Pharm. Sci. 2012, 101, 4018– 4023,  DOI: 10.1002/jps.23259
      63
      A simple confined impingement jets mixer for flash nanoprecipitation
      Han, Jing; Zhu, Zhengxi; Qian, Haitao; Wohl, Adam R.; Beaman, Charles J.; Hoye, Thomas R.; Macosko, Christopher W.
      Journal of Pharmaceutical Sciences (2012), 101 (10), 4018-4023CODEN: JPMSAE; ISSN:0022-3549. (John Wiley & Sons, Inc.)
      Johnson and Prud'homme (2003. AICHE J 49:2264-2282) introduced the confined impingement jets (CIJ) mixer to prep. nanoparticles loaded with hydrophobic compds. (e.g., drugs, inks, fragrances, or pheromones) via flash nanopptn. (FNP). We have modified the original CIJ design to allow hand operation, eliminating the need for a syringe pump, and we added a second antisolvent diln. stage. Impingement mixing requires equal flow momentum from two opposing jets, one contg. the drug in org. solvent and the other contg. an antisolvent, typically water. The subsequent diln. step in the new design allows rapid quenching with high antisolvent concn. that enhances nanoparticle stability. This new CIJ with diln. (CIJ-D) mixer is a simple, cheap, and efficient device to produce nanoparticles. We have made 55 nm diam. β-carotene nanoparticles using the CIJ-D mixer. They are stable and reproducible in terms of particle size and distribution. We have also compared the performance of our CIJ-D mixer with the vortex mixer, which can operate at unequal flow rates (Liu et al., 2008. Chem Eng Sci 63:2829-2842), to make β-carotene-contg. particles over a series of turbulent conditions. On the basis of dynamic light scattering measurements, the new CIJ-D mixer produces stable particles of a size similar to the vortex mixer. Our CIJ-D design requires less vol. and provides an easily operated and inexpensive tool to produce nanoparticles via FNP and to evaluate new nanoparticle formulation. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Assocn. J Pharm Sci.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XpvVers70%253D&md5=c5e9605fc18c6dfbb6818cfe3a8888f6
    64. 64
      Johnson, B. K.; Prud’homme, R. K. Mechanism for Rapid Self-Assembly of Block Copolymer Nanoparticles. Phys. Rev. Lett. 2003, 91, 118302,  DOI: 10.1103/PhysRevLett.91.118302
      64
      Mechanism for Rapid Self-Assembly of Block Copolymer Nanoparticles
      Johnson, Brian K.; Prud'homme, Robert K.
      Physical Review Letters (2003), 91 (11), 118302/1-118302/4CODEN: PRLTAO; ISSN:0031-9007. (American Physical Society)
      Amphiphilic block copolymers in soln. spontaneously self-assemble when the solvent quality for one block is selectively decreased. We demonstrate that, for supersatn. ratio changes [d(S)/dt] over 105 per s from equil., nanoparticles are obtained with a formation mechanism and size dependent on the jumping rate and magnitude. The threshold rate for homogeneous pptn. is detd. by the induction time of a particle, equiv. to the diffusion limited fusion of copolymer chains to form a corona of overlapping sol. brushes. Via detn. of the induction time with a novel confined impinging jets mixer and use of a scaling relation, the interfacial free energy of a block copolymer nanoparticle was measured for the first time.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt1Oqurw%253D&md5=465c945d7870908649f6f231a6677a98
    65. 65
      Daniel, S.; Kis, Z.; Kontoravdi, C.; Shah, N. Quality by Design for Enabling RNA Platform Production Processes. Trends Biotechnol 2022, 40, 1213– 1228,  DOI: 10.1016/j.tibtech.2022.03.012
      65
      Quality by Design for enabling RNA platform production processes
      Daniel, Simon; Kis, Zoltan; Kontoravdi, Cleo; Shah, Nilay
      Trends in Biotechnology (2022), 40 (10), 1213-1228CODEN: TRBIDM; ISSN:0167-7799. (Elsevier Ltd.)
      A review. RNA-based products have emerged as one of the most promising and strategic technologies for global vaccination, infectious disease control, and future therapy development. The assessment of crit. quality attributes (CQAs), product-process interactions, relevant process anal. technologies, and process modeling capabilities can feed into a robust Quality by Design (QbD) framework for future development, design, and control of manufg. processes. QbD implementation will help the RNA technol. reach its full potential and will be central to the development, pre-qualification, and regulatory approval of rapid response, disease-agnostic RNA platform prodn. processes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB38XpvVahurs%253D&md5=7b64c147111978920111452f652888dc
    66. 66
      Warne, N.; Ruesch, M.; Siwik, P.; Mensah, P.; Ludwig, J.; Hripcsak, M.; Godavarti, R.; Prigodich, A.; Dolsten, M. Delivering 3 Billion Doses of Comirnaty in 2021. Nat. Biotechnol. 2023, 41, 183– 188,  DOI: 10.1038/s41587-022-01643-1
      66
      Delivering 3 billion doses of Comirnaty in 2021
      Warne, Nicholas; Ruesch, Margaret; Siwik, Pamela; Mensah, Paul; Ludwig, John; Hripcsak, Michael; Godavarti, Ranga; Prigodich, Andrew; Dolsten, Mikael
      Nature Biotechnology (2023), 41 (2), 183-188CODEN: NABIF9; ISSN:1087-0156. (Nature Portfolio)
      Pfizer created a 'light-speed' approach to meet the challenge of vaccinating the world against COVID-19. It involved developing new strategies for all aspects of vaccine development, from sourcing materials and scaling up manufg. to transportation and dosing.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3sXis1Sjs7o%253D&md5=c0125b7d1eb92de3d174e35c99a37aec
    67. 67
      Chang, T. Z.; Stadmiller, S. S.; Staskevicius, E.; Champion, J. A. Effects of Ovalbumin Protein Nanoparticle Vaccine Size and Coating on Dendritic Cell Processing. Biomater Sci. 2017, 5, 223– 233,  DOI: 10.1039/C6BM00500D
      67
      Effects of ovalbumin protein nanoparticle vaccine size and coating on dendritic cell processing
      Chang, Timothy Z.; Stadmiller, Samantha S.; Staskevicius, Erika; Champion, Julie A.
      Biomaterials Science (2017), 5 (2), 223-233CODEN: BSICCH; ISSN:2047-4849. (Royal Society of Chemistry)
      Nanoparticle vaccine delivery platforms are a promising technol. for enhancing vaccine immunogenicity. Protein nanoparticles (PNPs), made entirely from antigen, have been shown to induce protective immune responses against influenza. However, the fundamental mechanisms by which PNPs enhance component protein immunogenicity are not understood. Here, we investigate the role of size and coating of model ovalbumin (OVA) PNPs on particle uptake and trafficking, as well as on inflammation and maturation factor expression in dendritic cells (DCs) in vitro. OVA PNPs enhance antigen uptake in a size-independent manner, and experience attenuated endosomal acidification as compared to sol. OVA. OVA PNPs also trigger Fc receptor upregulation. Expression of cytokines IL-1β and TNF-α were PNP size- and coating-dependent, with small (∼270 nm) nanoparticles triggering greater inflammatory cytokine prodn. than large (∼560 nm) particles. IL-1β expression by DCs in response to PNP stimulation implies activation of the inflammasome, a pathway known to be activated by certain types of nanoparticulate adjuvants. The attenuated acidification and pro-inflammatory profile generated by PNPs in DCs demonstrate that phys. biomaterial properties can modulate dendritic cell-mediated antigen processing and adjuvancy. In addn. to nanoparticles' enhancement of DC antigen uptake, our work suggests that vaccine nanoparticle size and coating are uptake-independent modulators of immunogenicity.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvF2gurnK&md5=2847bc4357609887cd5580a2ae9eef75
    68. 68
      Thomas, S. N.; Schudel, A. Overcoming Transport Barriers for Interstitial-, Lymphatic-, and Lymph Node-Targeted Drug Delivery. Curr. Opin Chem. Eng. 2015, 7, 65– 74,  DOI: 10.1016/j.coche.2014.11.003
      68
      Overcoming transport barriers for interstitial-, lymphatic-, and lymph node-targeted drug delivery
      Thomas Susan N; Schudel Alex
      Current opinion in chemical engineering (2015), 7 (), 65-74 ISSN:2211-3398.
      Despite drug formulation improving circulation times and targeting, efficacy is stymied by inadequate penetration into and retention within target tissues. This review highlights the barriers restricting delivery to the connective tissue interstitium, lymphatics, and lymph nodes as well as advances in engineering drug carriers to overcome these delivery challenges. Three-dimensional tissue physiology is discussed in the context of providing material design principles for delivery to these tissues; in particular the influence of interstitial and lymphatic flows as well as differential permeabilities of the blood and lymphatic capillaries. Key examples of materials with different characteristics developed to overcome these transport barriers are discussed as well as potential areas for further development.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2srotF2rsQ%253D%253D&md5=3253ad4ef935260a93f650e74b980196
    69. 69
      Munson, M. J.; O’Driscoll, G.; Silva, A. M.; Lazaro-Ibanez, E.; Gallud, A.; Wilson, J. T.; Collen, A.; Esbjorner, E. K.; Sabirsh, A. A High-Throughput Galectin-9 Imaging Assay for Quantifying Nanoparticle Uptake, Endosomal Escape and Functional RNA Delivery. Commun. Biol. 2021, 4, 211,  DOI: 10.1038/s42003-021-01728-8
      69
      A high-throughput Galectin-9 imaging assay for quantifying nanoparticle uptake, endosomal escape and functional RNA delivery
      Munson, Michael J.; O'Driscoll, Gwen; Silva, Andreia M.; Lazaro-Ibanez, Elisa; Gallud, Audrey; Wilson, John T.; Collen, Anna; Esbjoerner, Elin K.; Sabirsh, Alan
      Communications Biology (2021), 4 (1), 211CODEN: CBOIDQ; ISSN:2399-3642. (Nature Research)
      RNA-based therapies have great potential to treat many undruggable human diseases. However, their efficacy, in particular for mRNA, remains hampered by poor cellular delivery and limited endosomal escape. Development and optimization of delivery vectors, such as lipid nanoparticles (LNPs), are impeded by limited screening methods to probe the intracellular processing of LNPs in sufficient detail. We have developed a high-throughput imaging-based endosomal escape assay utilizing a Galectin-9 reporter and fluorescently labeled mRNA to probe correlations between nanoparticle-mediated uptake, endosomal escape frequency, and mRNA translation. Furthermore, this assay has been integrated within a screening platform for optimization of lipid nanoparticle formulations. We show that Galectin-9 recruitment is a robust, quant. reporter of endosomal escape events induced by different mRNA delivery nanoparticles and small mols. We identify nanoparticles with superior escape properties and demonstrate cell line variances in endosomal escape response, highlighting the need for fine-tuning of delivery formulations for specific applications.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3MXhtV2iurvI&md5=2f6c6521ab150ffdcc94a614266cd245
    70. 70
      Shae, D.; Becker, K. W.; Christov, P.; Yun, D. S.; Lytton-Jean, A. K. R.; Sevimli, S.; Ascano, M.; Kelley, M.; Johnson, D. B.; Balko, J. M.; Wilson, J. T. Endosomolytic Polymersomes Increase the Activity of Cyclic Dinucleotide STING Agonists to Enhance Cancer Immunotherapy. Nat. Nanotechnol 2019, 14, 269– 278,  DOI: 10.1038/s41565-018-0342-5
      70
      Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy
      Shae, Daniel; Becker, Kyle W.; Christov, Plamen; Yun, Dong Soo; Lytton-Jean, Abigail K. R.; Sevimli, Sema; Ascano, Manuel; Kelley, Mark; Johnson, Douglas B.; Balko, Justin M.; Wilson, John T.
      Nature Nanotechnology (2019), 14 (3), 269-278CODEN: NNAABX; ISSN:1748-3387. (Nature Research)
      Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) are a promising class of immunotherapeutics that activate innate immunity to increase tumor immunogenicity. However, the efficacy of CDNs is limited by drug delivery barriers, including poor cellular targeting, rapid clearance and inefficient transport to the cytosol where STING is localized. Here, we describe STING-activating nanoparticles (STING-NPs)-rationally designed polymersomes for enhanced cytosolic delivery of the endogenous CDN ligand for STING, 2'3' cGMP-adenosine monophosphate (cGAMP). STING-NPs increase the biol. potency of cGAMP, enhance STING signaling in the tumor microenvironment and sentinel lymph node, and convert immunosuppressive tumors to immunogenic, tumoricidal microenvironments. This leads to enhanced therapeutic efficacy of cGAMP, inhibition of tumor growth, increased rates of long-term survival, improved response to immune checkpoint blockade and induction of immunol. memory that protects against tumor rechallenge. We validate STING-NPs in freshly isolated human melanoma tissue, highlighting their potential to improve clin. outcomes of immunotherapy.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmtVGitbo%253D&md5=4b95f1d3ac44492fd975fc9e37bcec58
    71. 71
      Zheng, S.; Wang, W.; Aldahdooh, J.; Malyutina, A.; Shadbahr, T.; Tanoli, Z.; Pessia, A.; Tang, J. Synergyfinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets. Genomics Proteomics Bioinformatics 2022, 20, 587– 596,  DOI: 10.1016/j.gpb.2022.01.004
      71
      SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets
      Zheng Shuyu; Wang Wenyu; Aldahdooh Jehad; Malyutina Alina; Shadbahr Tolou; Tanoli Ziaurrehman; Pessia Alberto; Tang Jing
      Genomics, proteomics & bioinformatics (2022), 20 (3), 587-596 ISSN:.
      Combinatorial therapies have been recently proposed to improve the efficacy of anticancer treatment. The SynergyFinder R package is a software used to analyze pre-clinical drug combination datasets. Here, we report the major updates to the SynergyFinder R package for improved interpretation and annotation of drug combination screening results. Unlike the existing implementations, the updated SynergyFinder R package includes five main innovations. 1) We extend the mathematical models to higher-order drug combination data analysis and implement dimension reduction techniques for visualizing the synergy landscape. 2) We provide a statistical analysis of drug combination synergy and sensitivity with confidence intervals and P values. 3) We incorporate a synergy barometer to harmonize multiple synergy scoring methods to provide a consensus metric for synergy. 4) We evaluate drug combination synergy and sensitivity to provide an unbiased interpretation of the clinical potential. 5) We enable fast annotation of drugs and cell lines, including their chemical and target information. These annotations will improve the interpretation of the mechanisms of action of drug combinations. To facilitate the use of the R package within the drug discovery community, we also provide a web server at www.synergyfinderplus.org as a user-friendly interface to enable a more flexible and versatile analysis of drug combination data.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB2M7jslymtA%253D%253D&md5=586c7516cf1d71a67d4788d4e640754e
    72. 72
      Mouries, J.; Moron, G.; Schlecht, G.; Escriou, N.; Dadaglio, G.; Leclerc, C. Plasmacytoid Dendritic Cells Efficiently Cross-Prime Naive T Cells in Vivo after TLR Activation. Blood 2008, 112, 3713– 3722,  DOI: 10.1182/blood-2008-03-146290
      72
      Plasmacytoid dendritic cells efficiently cross-prime naive T cells in vivo after TLR activation
      Mouries, Juliette; Moron, Gabriel; Schlecht, Geraldine; Escriou, Nicolas; Dadaglio, Gilles; Leclerc, Claude
      Blood (2008), 112 (9), 3713-3722CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)
      Cross-presentation is a crucial mechanism in tumoral and microbial immunity because it allows internalized cell assocd. or exogenous antigens (Ags) to be delivered into the major histocompatibility complex I pathway. This pathway is important for the development of CD8+ T-cell responses and for the induction of tolerance. In mice, cross-presentation is considered to be a unique property of CD8α+ conventional dendritic cells (DCs). Here we show that splenic plasmacytoid DCs (pDCs) efficiently capture exogenous Ags in vivo but are not able to cross-present these Ags at steady state. However, in vitro and in vivo stimulation by Toll-like receptor-7, or -9 or viruses licenses pDCs to cross-present sol. or particulate Ags by a transporter assocd. with antigen processing-dependent mechanism. Induction of cross-presentation confers to pDCs the ability to generate efficient effector CD8+ T-cell responses against exogenous Ags in vivo, showing that pDCs may play a crucial role in induction of adaptive immune responses against pathogens that do not infect tissues of hemopoietic origin. This study provides the first evidence for an in vivo role of splenic pDCs in Ag cross-presentation and T-cell cross-priming and suggests that pDCs may constitute an attractive target to boost the efficacy of vaccines based on cytotoxic T lymphocyte induction.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlCntrvF&md5=6484bd424f61a2bcf69ee7076b403ea6
    73. 73
      Villadangos, J. A.; Young, L. Antigen-Presentation Properties of Plasmacytoid Dendritic Cells. Immunity 2008, 29, 352– 361,  DOI: 10.1016/j.immuni.2008.09.002
      73
      Antigen-presentation properties of plasmacytoid dendritic cells
      Villadangos, Jose A.; Young, Louise
      Immunity (2008), 29 (3), 352-361CODEN: IUNIEH; ISSN:1074-7613. (Cell Press)
      A review. One of the remaining enigmas of the dendritic cell (DC) network is the potential contribution of plasmacytoid DCs (pDCs) to antigen presentation. Although the antigen-presentation capacity of conventional DCs (cDCs) is clearly defined, pDCs are generally attributed as having little, if any, antigen-presentation function. Instead, pDCs are regarded as immunomodulating cells, capable of directing the immune response through their secretion of large amts. of type I interferons. Here, the authors examine the evidence for a potential role of pDC in antigen capture, processing, and presentation to T cells at sites of infection and in the lymph nodes.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtF2jtLvL&md5=81e1c944723cfa0bc4117416b558dad0
    74. 74
      Hildner, K.; Edelson, B. T.; Purtha, W. E.; Diamond, M.; Matsushita, H.; Kohyama, M.; Calderon, B.; Schraml, B. U.; Unanue, E. R.; Diamond, M. S.; Schreiber, R. D.; Murphy, T. L.; Murphy, K. M. Batf3 Deficiency Reveals a Critical Role for CD8α+ Dendritic Cells in Cytotoxic T Cell Immunity. Science 2008, 322, 1097– 1100,  DOI: 10.1126/science.1164206
      74
      Batf3 Deficiency Reveals a Critical Role for CD8α+ Dendritic Cells in Cytotoxic T Cell Immunity
      Hildner, Kai; Edelson, Brian T.; Purtha, Whitney E.; Diamond, Mark; Matsushita, Hirokazu; Kohyama, Masako; Calderon, Boris; Schraml, Barbara U.; Unanue, Emil R.; Diamond, Michael S.; Schreiber, Robert D.; Murphy, Theresa L.; Murphy, Kenneth M.
      Science (Washington, DC, United States) (2008), 322 (5904), 1097-1100CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Although in vitro observations suggest that cross-presentation of antigens is mediated primarily by CD8α+ dendritic cells, in vivo anal. has been hampered by the lack of systems that selectively eliminate this cell lineage. We show that deletion of the transcription factor Batf3 ablated development of CD8α+ dendritic cells, allowing us to examine their role in immunity in vivo. Dendritic cells from Batf3-/- mice were defective in cross-presentation, and Batf3-/- mice lacked virus-specific CD8+ T cell responses to West Nile virus. Importantly, rejection of highly immunogenic syngeneic tumors was impaired in Batf3-/- mice. These results suggest an important role for CD8α+ dendritic cells and cross-presentation in responses to viruses and in tumor rejection.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtlGhu7fF&md5=5edf74e0adedb0e092d59a241a711784
    75. 75
      Kaech, S. M.; Wherry, E. J.; Ahmed, R. Effector and Memory T-Cell Differentiation: Implications for Vaccine Development. Nat. Rev. Immunol 2002, 2, 251– 262,  DOI: 10.1038/nri778
      75
      Effector and memory T-cell differentiation: implications for vaccine development
      Kaech, Susan M.; Wherry, E. John; Ahmed, Rafi
      Nature Reviews Immunology (2002), 2 (4), 251-262CODEN: NRIABX; ISSN:1474-1733. (Nature Publishing Group)
      A review. Recent work shows that after stimulation with antigen, CD4+ and CD8+ T cells embark on a program of proliferation that is closely linked with the acquisition of effector functions and leads ultimately to memory-cell formation. Here, we discuss the signals required for commitment to this program of development and the factors that might influence its progression. Models of the pathways of effector and memory T-cell differentiation are discussed, and we highlight the implications of this new understanding for the optimization of vaccine strategies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XjtFKhtrc%253D&md5=7a63c84ffcfeae8b4362befd059980e3
    76. 76
      Taylor, M. A.; Hughes, A. M.; Walton, J.; Coenen-Stass, A. M. L.; Magiera, L.; Mooney, L.; Bell, S.; Staniszewska, A. D.; Sandin, L. C.; Barry, S. T. Longitudinal Immune Characterization of Syngeneic Tumor Models to Enable Model Selection for Immune Oncology Drug Discovery. J. Immunother Cancer 2019, 7, 328,  DOI: 10.1186/s40425-019-0794-7
      76
      Longitudinal immune characterization of syngeneic tumor models to enable model selection for immune oncology drug discovery
      Taylor Molly A; Hughes Adina M; Walton Josephine; Coenen-Stass Anna M L; Magiera Lukasz; Mooney Lorraine; Bell Sigourney; Staniszewska Anna D; Sandin Linda C; Barry Simon T; Watkins Amanda; Carnevalli Larissa S; Hardaker Elizabeth L; Mooney Lorraine
      Journal for immunotherapy of cancer (2019), 7 (1), 328 ISSN:.
      BACKGROUND: The ability to modulate immune-inhibitory pathways using checkpoint blockade antibodies such as αPD-1, αPD-L1, and αCTLA-4 represents a significant breakthrough in cancer therapy in recent years. This has driven interest in identifying small-molecule-immunotherapy combinations to increase the proportion of responses. Murine syngeneic models, which have a functional immune system, represent an essential tool for pre-clinical evaluation of new immunotherapies. However, immune response varies widely between models and the translational relevance of each model is not fully understood, making selection of an appropriate pre-clinical model for drug target validation challenging. METHODS: Using flow cytometry, O-link protein analysis, RT-PCR, and RNAseq we have characterized kinetic changes in immune-cell populations over the course of tumor development in commonly used syngeneic models. RESULTS: This longitudinal profiling of syngeneic models enables pharmacodynamic time point selection within each model, dependent on the immune population of interest. Additionally, we have characterized the changes in immune populations in each of these models after treatment with the combination of α-PD-L1 and α-CTLA-4 antibodies, enabling benchmarking to known immune modulating treatments within each model. CONCLUSIONS: Taken together, this dataset will provide a framework for characterization and enable the selection of the optimal models for immunotherapy combinations and generate potential biomarkers for clinical evaluation in identifying responders and non-responders to immunotherapy combinations.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MfksVSntA%253D%253D&md5=7b3308ccad3e1cbb161737db47069240
    77. 77
      Wang-Bishop, L.; Wehbe, M.; Shae, D.; James, J.; Hacker, B. C.; Garland, K.; Chistov, P. P.; Rafat, M.; Balko, J. M.; Wilson, J. T. Potent Sting Activation Stimulates Immunogenic Cell Death to Enhance Antitumor Immunity in Neuroblastoma. J. Immunother Cancer 2020, 8, e000282,  DOI: 10.1136/jitc-2019-000282
      There is no corresponding record for this reference.
    78. 78
      Kilchrist, K. V.; Dimobi, S. C.; Jackson, M. A.; Evans, B. C.; Werfel, T. A.; Dailing, E. A.; Bedingfield, S. K.; Kelly, I. B.; Duvall, C. L. Gal8 Visualization of Endosome Disruption Predicts Carrier-Mediated Biologic Drug Intracellular Bioavailability. ACS Nano 2019, 13, 1136– 1152,  DOI: 10.1021/acsnano.8b05482
      78
      Gal8 Visualization of Endosome Disruption Predicts Carrier-Mediated Biologic Drug Intracellular Bioavailability
      Kilchrist, Kameron V.; Dimobi, Somtochukwu C.; Jackson, Meredith A.; Evans, Brian C.; Werfel, Thomas A.; Dailing, Eric A.; Bedingfield, Sean K.; Kelly, Isom B.; Duvall, Craig L.
      ACS Nano (2019), 13 (2), 1136-1152CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Endolysosome entrapment is one of the key barriers to the therapeutic use of biol. drugs that act intracellularly. The screening of prospective nanoscale endosome-disrupting delivery technologies is currently limited by methods that are indirect and cumbersome. Here, we statistically validate Galectin 8 (Gal8) intracellular tracking as a superior approach that is direct, quant., and predictive of therapeutic cargo intracellular bioactivity through in vitro high-throughput screening and in vivo validation. Gal8 is a cytosolically dispersed protein that, when endosomes are disrupted, redistributes by binding to glycosylation moieties selectively located on the inner face of endosomal membranes. The quant. redistribution of a Gal8 fluorescent fusion protein from the cytosol into endosomes is demonstrated as a real-time, live-cell assessment of endosomal integrity that does not require labeling or modification of either the carrier or the biol. drug and that allows quant. distinction between closely related, endosome-disruptive drug carriers. Through screening two families of siRNA polymeric carrier compns. at varying dosages, we show that Gal8 endosomal recruitment correlates strongly (r = 0.95 and p < 10-4) with intracellular siRNA bioactivity. Through this screen, we gathered insights into how compn. and mol. wt. affect endosome disruption activity of poly[(ethylene glycol)-b-[(2-(dimethylamino)ethyl methacrylate)-co-(Bu methacrylate)]] [PEG-(DMAEMA-co-BMA)] siRNA delivery systems. Addnl. studies showed that Gal8 recruitment predicts intracellular bioactivity better than current std. methods such as Lysotracker colocalization (r = 0.35, not significant), pH-dependent hemolysis (not significant), or cellular uptake (r = 0.73 and p < 10-3). Importantly, the Gal8 recruitment method is also amenable to fully objective high-throughput screening using automated image acquisition and quant. image anal., with a robust estd. Z' of 0.6 (whereas assays with Z' > 0 have high-throughput screening utility). Finally, we also provide measurements of in vivo endosomal disruption based on Gal8 visualization (p < 0.03) of a nanocarrier formulation confirmed to produce significant cytosolic delivery and bioactivity of siRNA within tumors (p < 0.02). In sum, this report establishes the utility of Gal8 subcellular tracking for the rapid optimization and high-throughput screening of the endosome disruption potency of intracellular delivery technologies.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht12qs7w%253D&md5=35d2d7494c1933249faf76094de990cf

  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.3c04471.

    • Supplementary data describing polymer characterization, nanovaccine drug loading and sizing properties, BMDC costimulatory molecule expression and pro-inflammatory cytokine secretion, Loewe synergy scores, cellular uptake, tumor growth curves, and flow cytometry gating strategies (PDF)


    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.