Redirection of Genetically Engineered CAR-T Cells Using Bifunctional Small Molecules
2015
Kim, Min-su | Ma, Jennifer S. Y. | Yun, Hwayoung | Cao, Yu | Kim, Ji-Young | Chi, Víctor | Wang, Danling | Woods, Ashley | Sherwood, Lance | Caballero, Dawna | González, José | Schultz, Peter G. | Young, Travis S. | Kim, Chan Hyuk
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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