工程改造共刺激的結(jié)構(gòu)設(shè)計(jì)決定了CAR-T細(xì)胞的抗腫瘤反應(yīng)動(dòng)力學(xué)和持久性

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

摘要:

細(xì)胞工程是快速產(chǎn)生抗腫瘤細(xì)胞的有力手段。第二代嵌合抗原受體的共刺激特性（CARs）決定了整體的T細(xì)胞過繼移植的能力。利用一個(gè)體內(nèi)的“壓力測(cè)試”來挑戰(zhàn)CD19靶向T細(xì)胞，我們研究了7個(gè)不同的由CD28和/或者4-1BB共刺激產(chǎn)生的CAR結(jié)構(gòu)所對(duì)應(yīng)的功能性和持久性。有一種配置，它采用兩個(gè)信號(hào)域（CD28和CD3ζ）和4-1BB配體，提供出了zui高的療效，展現(xiàn)了平衡的抗腫瘤能力并增加了T細(xì)胞的持續(xù)性，它伴隨著一個(gè)升高的CD8/CD4比例和減弱的衰老性。值得注意的是，IRF7/IFNβ途徑具有*化的抗腫瘤活性。因此，1928z-41BBLT細(xì)胞擁有非常強(qiáng)大的內(nèi)在品質(zhì)和免疫調(diào)節(jié)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.