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J Am Chem Soc. 2015 Mar 4;137(8):2832-5. doi: 10.1021/jacs.5b00106. Epub 2015 Feb 24.

Redirection of genetically engineered CAR-T cells using bifunctional small molecules.

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1
California Institute for Biomedical Research , 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.

Abstract

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.

PMID:
25692571
DOI:
10.1021/jacs.5b00106
[Indexed for MEDLINE]

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