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

被引：145

作者：

Kim, Min Soo ^{[1
]}

Ma, Jennifer S. Y. ^{[1
]}

Yun, Hwayoung ^{[2
,3
]}

Cao, Yu ^{[2
,3
]}

Kim, Ji Young ^{[1
]}

Chi, Victor ^{[1
]}

Wang, Danling ^{[1
]}

Woods, Ashley ^{[1
]}

Sherwood, Lance ^{[1
]}

Caballero, Dawna ^{[1
]}

Gonzalez, Jose ^{[1
]}

Schultz, Peter G. ^{[1
,2
,3
]}

Young, Travis S. ^{[1
]}

Kim, Chan Hyuk ^{[1
]}

机构：

[1] Calif Inst Biomed Res, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[3] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2015年 / 137卷 / 08期

关键词：

FOLATE RECEPTOR-ALPHA; ANTIGEN RECEPTOR; ANTITUMOR-ACTIVITY; CANCER; IMMUNOTHERAPY; EXPRESSION; MALIGNANCIES; CARCINOMA; TOXICITY; LEUKEMIA;

D O I：

10.1021/jacs.5b00106

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页码：2832 / 2835

页数：4

共 28 条

[1] Chimeric Antigen Receptor Therapy for Cancer [J].