工程改造共刺激的结构设计决定了CAR-T细胞

工程改造共刺激的结构设计决定了CAR-T细胞的抗肿瘤反应动力学和持久性

Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells.

摘要:

细胞工程是快速产生抗肿瘤细胞的有力手段。第二代嵌合抗原受体的共刺激特性（CARs）决定了整体的T细胞过继移植的能力。利用一个体内的“压力测试”来挑战CD19靶向T细胞，我们研究了7个不同的由CD28和/或者4-1BB共刺激产生的CAR结构所对应的功能性和持久性。有一种配置，它采用两个信号域（CD28和CD3ζ）和4-1BB配体，提供出了zui高的疗效，展现了平衡的抗肿瘤能力并增加了T细胞的持续性，它伴随着一个升高的CD8/CD4比例和减弱的衰老性。值得注意的是，IRF7/IFNβ途径具有*化的抗肿瘤活性。因此，1928z-41BBLT细胞拥有非常强大的内在品质和免疫调节能力。

Abstract

T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo "stress test" to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.