构建新型IL-2依赖的表达CD25的第二代反式嵌合抗原受体的研究

嵌合抗原受体（CARs）是一类新的具有巨大抗肿瘤潜力的“活药”。结合了活化和共刺激信号转导区的第二代CARs决定了CAR T细胞的抗肿瘤功能、分化潜能和存活期。大多数临床研究表明，第一代CAR T细胞不会释放较强的包括白细胞介素（IL）-2在内的细胞因子，也不支持CAR T细胞增殖。本研究拟以安全性较高的第一代CAR为基础，构建一种新型的IL-2依赖的表达CD25的第二代反式嵌合抗原受体。这种新型的第二代反式CAR T细胞的持续存活可以依赖于外源性IL-2的剂量。更重要的是抗CD25的单克隆抗体（mAb）可以特异性地靶向消除表达CD25的新型CAR T细胞，这样就既达到了抗肿瘤的目的又避免了传统CAR T细胞常见的脱靶效应损伤，从而为CAR T细胞的抗肿瘤免疫治疗提供了更加安全的平台。

Chimeric antigen receptors (CARs) are a new class of "living drugs" with great potential for cancer immunotherapy. The combined activating and co-stimulatory domains incorporated in second-generation CARs critically determine the function, differentiation and persistence of CAR T cells. Most clinical studies demonstrated that first-generation CAR T cells failed to elicit a robust cytokine response, including interleukin (IL)-2, and support T-cell expansion in patients. This study will construct a novel IL-2 dependent CD25 expressing second-generation trans chimeric antigen receptor based on safe first-generation CAR. The persistence of this novel second generation trans CAR modified T cells may depends on the dose of exogenous IL-2 . Importantly, anti-CD25 monoclonal antibody(mAb) may specifically target and eliminate novel CAR T cells expressing CD25. This novel design may provide a safer platform for CARs based cancer immunotherapy.