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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

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发表于 2015-11-9 22:24:04 | 显示全部楼层 |阅读模式
Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells.
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
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7个不同的由CD28/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(CD28CD3ζ)和4-1BB配体,提供出了最高的疗效,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途径具有最优化的抗肿瘤活性。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.

 楼主| 发表于 2015-11-9 22:56:03 | 显示全部楼层
爱康得生物医学技术(苏州)有限公司,专注免疫治疗。
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