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

• Published in: Journal of the American Chemical Society 2015-03, Vol.137 (8), p.2832-2835
• Main Authors: Kim, Min Soo, Ma, Jennifer S. Y, Yun, Hwayoung, Cao, Yu, Kim, Ji Young, Chi, Victor, Wang, Danling, Woods, Ashley, Sherwood, Lance, Caballero, Dawna, Gonzalez, Jose, Schultz, Peter G, Young, Travis S, Kim, Chan Hyuk
• Format: Article
• Language: English
• Subjects: Cell Engineering; Fluorescein-5-isothiocyanate - chemistry; Folic Acid - chemistry; Folic Acid - metabolism; Folic Acid Transporters - metabolism; HEK293 Cells; Humans; KB Cells; Receptors, Antigen, T-Cell - genetics; T-Lymphocytes - cytology; T-Lymphocytes - metabolism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.5b00106

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.