Bellicum Pharmaceuticals, Houston, TX 77030, USA.
Bellicum Pharmaceuticals, Houston, TX 77030, USA.
Mol Ther. 2017 Sep 6;25(9):2176-2188. doi: 10.1016/j.ymthe.2017.06.014. Epub 2017 Jul 8.
Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4 and CD8 T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function. Here, we present a novel strategy to activate TLR and CD40 signaling in human T cells using inducible MyD88/CD40 (iMC), which can be triggered in vivo via the synthetic dimerizing ligand, rimiducid, to provide potent costimulation to CAR-modified T cells. Importantly, the concurrent activation of iMC (with rimiducid) and CAR (by antigen recognition) is required for interleukin (IL)-2 production and robust CAR-T cell expansion and may provide a user-controlled mechanism to amplify CAR-T cell levels in vivo and augment anti-tumor efficacy.
表达嵌合抗原受体 (CAR) 的 T 细胞的抗肿瘤功效取决于其特异性、存活以及过继转移后的体内扩增。T 细胞中的 Toll 样受体 (TLR) 和 CD40 信号可以改善病原体挑战或移植物抗宿主病 (GvHD) 环境下抗原特异性 CD4 和 CD8 T 细胞的持久性并驱动其增殖，表明这些共刺激途径可能被重新用于改善 CAR-T 细胞的持久性和功能。在这里，我们提出了一种使用诱导型 MyD88/CD40（iMC）在人 T 细胞中激活 TLR 和 CD40 信号的新策略，该策略可以通过合成二聚化配体 rimiducid 在体内触发，从而为 CAR 修饰的 T 细胞提供有效的共刺激。重要的是，iMC（用 rimiducid 触发）和 CAR（通过抗原识别）的同时激活对于白细胞介素 (IL)-2 的产生和 CAR-T 细胞的扩增至关重要，并且可能提供一种可由使用者控制的机制，以在体内扩增 CAR-T 细胞水平并增强抗肿瘤功效。
