Bcl-2通过减少激活诱导的细胞凋亡增强嵌合抗原受体T细胞的持久性。

Bcl-2 Enhances Chimeric Antigen Receptor T Cell Persistence by Reducing Activation-Induced Apoptosis.

作者信息

Wang Haiyong, Han Ping, Qi Xinyue, Li Fanlin, Li Min, Fan Lilv, Zhang Huihui, Zhang Xiaoqing, Yang Xuanming

机构信息

Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.

Joint International Research Laboratory of Metabolic & Developmental Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.

出版信息

Cancers (Basel). 2021 Jan 8;13(2):197. doi: 10.3390/cancers13020197.

PURPOSE

To evaluate the potential added value of integrating anti-apoptotic molecules for improving the anti-tumor activity of CAR-T cells.

METHODS

Four small molecules inhibiting apoptosis were tested for their ability to prevent activated induced CAR-T cell death. Five CD20-targeting, CD137 (4-1BB) and CD3ζ integrated CAR-T cells (20BBZ) with constitutively expressed anti-apoptotic genes were established, and we screened out the strongest proliferation enhancer: Bcl-2. The memory subtype and the exhaustion markers of CAR-T cells were analyzed. The anti-tumor activities of Bcl-2 integrating CAR-T cells (20BBZ-Bcl-2) were evaluated in vitro and in a mouse xenograft lymphoma model.

CONCLUSION

The 20BBZ-Bcl-2 CAR-T cells showed improved proliferation ability compared to 20BBZ CAR-T cells in vitro. In addition, activation-induced apoptosis was reduced in the 20BBZ-Bcl-2 CAR-T cells. Consistent with the enhanced proliferation in vitro, 20BBZ-Bcl-2 CAR-T cells exhibited improved anti-tumor activity in a mouse xenograft lymphoma model.

目的

评估整合抗凋亡分子对提高嵌合抗原受体T细胞（CAR-T细胞）抗肿瘤活性的潜在附加价值。

方法

测试了四种抑制凋亡的小分子阻止活化诱导的CAR-T细胞死亡的能力。构建了五个整合了靶向CD20、CD137（4-1BB）和CD3ζ且组成性表达抗凋亡基因的CAR-T细胞（20BBZ），并筛选出最强的增殖增强剂：Bcl-2。分析了CAR-T细胞的记忆亚型和耗竭标志物。在体外和小鼠异种移植淋巴瘤模型中评估了整合Bcl-2的CAR-T细胞（20BBZ-Bcl-2）的抗肿瘤活性。