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嵌合式抗原受体T细胞的向和细胞毒性与PD1外膜域移植

Ang Zhang^1,2, Shenyu Wang^1,3, Yao Sun³

¹Academy of Military Medical Sciences, Academy of Military Sciences, Beijing, 100850, PR China.

Experimental hematology & oncology

|September 30, 2023

概括

针对CD19和编程细胞死亡1合体1 (PDL1) 的工程化模拟抗原受体 (CAR) -T细胞显示出改善的抗瘤活性. 这种新的CAR设计有效地克服了PD1介导的免疫抑制,并降低了毒性.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
生物技术是生物技术.

背景情况:

编程细胞死亡蛋白1 (PD1) 介导的免疫抑制限制了仿真抗原受体 (CAR) -T细胞治疗的疗效.
结合PD1/PDL1轴阻塞和CAR-T疗法是有希望的,但需要优化,低毒性方法.
直接针对PDL1可能会导致系统性不良影响,需要采取替代策略.

研究的目的:

设计新的CAR结构,能够识别瘤抗原和PDL1.
评估与PD1域设计的CAR的疗效和安全性.
评估这些新型CARs在克服CD19阳性,PDL1阳性瘤中的PD1-介导免疫抑制的潜力.

主要方法:

通过将PD1域移植到针对CD19的第二代 (2G) CAR中来设计新的CAR.
开发了两个CAR变体:PE CAR (PD1外膜域直接连接到跨膜域) 和PE8HT CAR (PD1EMD通过CD8链域连接).
在体外和体内使用CD19/PDL1-过度表达瘤模型评估CAR疗效,包括细胞毒性,细胞因子释放和非标效应.

主要成果:

与2G CAR-T细胞相比,PE CAR表现出增强的细胞毒性和减少对CD19+/PDL1+瘤细胞的细胞因子释放.
PE CAR对CD19-/PDL1+瘤细胞没有显示出非标效应.
流细胞测量,RNA测序和代谢分析显示,在遇到细胞后,PE CAR-T细胞的分化得到改善,疲劳减少和亡表型减少.

结论:

与PD1接种的CARs表现出增强的抗瘤活性,细胞因子释放减少,并且没有PD1相关的目标外毒性.
新的CAR设计有效地解决了CD19和PDL1共同过度表达瘤模型中的PD1-介导免疫抑制.
这一策略有可能改善相关癌症的CAR-T细胞治疗结果.

关键词:

化学抗原受体T细胞的T细胞.链域名链域名链域名目标外的毒性目标外的毒性这就是PD1 PD1.瘤微环境是一个微环境.

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