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

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.

• Authors: Min Soo Kim, Jennifer S Y Ma, Hwayoung Yun, Yu Cao, Ji Young Kim, Victor Chi, Danling Wang, Ashley Woods, Lance Sherwood, Dawna Caballero, Jose Gonzalez, Peter G Schultz, Travis S Young, Chan Hyuk Kim
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 137 Issue 8 Pg. 2832-5 (Mar 04 2015) ISSN: 1520-5126 [Electronic] United States
• PMID: 25692571 (Publication Type: Journal Article)

Chemical References

• Folic Acid Transporters
• Receptors, Antigen, T-Cell
• Folic Acid
• Fluorescein-5-isothiocyanate

Topics

• Cell Engineering
• Fluorescein-5-isothiocyanate (chemistry)
• Folic Acid (chemistry, metabolism)
• Folic Acid Transporters (metabolism)
• HEK293 Cells
• Humans
• KB Cells
• Receptors, Antigen, T-Cell (genetics)
• T-Lymphocytes (cytology, metabolism)