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Redirection of Genetically Engineered CAR-T Cells Using Bifunctional Small Molecules

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Am. Chem. Soc. 2015, 137, 8, 2832-2835
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    Redirection of Genetically Engineered CAR-T Cells Using Bifunctional Small Molecules
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    † California Institute for Biomedical Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States
    ‡ Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
    *[email protected]
    *[email protected]
    *[email protected]
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    Cite this: J. Am. Chem. Soc. 2015, 137, 8, 2832–2835
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    https://doi.org/10.1021/jacs.5b00106
    Published February 18, 2015
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    Chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) provide a potent antitumor response and have become a promising treatment option for cancer. However, despite their efficacy, CAR-T cells are associated with significant safety challenges related to the inability to control their activation and expansion and terminate their response. Herein, we demonstrate that a bifunctional small molecule “switch” consisting of folate conjugated to fluorescein isothiocyanate (folate-FITC) can redirect and regulate FITC-specific CAR-T cell activity toward folate receptor (FR)-overexpressing tumor cells. This system was shown to be highly cytotoxic to FR-positive cells with no activity against FR-negative cells, demonstrating the specificity of redirection by folate-FITC. Anti-FITC-CAR-T cell activation and proliferation was strictly dependent on the presence of both folate-FITC and FR-positive cells and was dose titratable with folate-FITC switch. This novel treatment paradigm may ultimately lead to increased safety for CAR-T cell immunotherapy.

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    Supplementary Figures S1–S4 and detailed materials and methods. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 137 publications.

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    Cite this: J. Am. Chem. Soc. 2015, 137, 8, 2832–2835
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