基于细胞外囊泡精确调控CAR-T细胞IL2Rβ/IL2Rγ信号的效应及分子机制研究

嵌合抗原受体T（CAR-T）细胞疗法在治疗难治/复发性 B细胞肿瘤中展示出良好的效果，但CAR-T细胞体内持久性差引发的复发率高的问题亟待解决。申请人团队前期研究和最新文献显示：激活CAR-T细胞中的IL2Rβ/IL2Rγ介导的信号通路或可提高其在体内的持久性，从而改善治疗后复发率高的问题，但如何精确的激活IL2Rβ/IL2Rγ通路及其调控CAR-T细胞的作用机制尚未报道。本项目拟立足于此，综合运用囊泡递送系统、CAR-T制备平台、NPG荷瘤小鼠模型等材料和技术，开发囊泡定向递送CD19抗原和Neo-2/15因子至anti-CD19 CAR-T细胞技术，精确激活IL2Rβ/IL2Rγ通路，探究该通路调控CAR-T细胞增殖与持久的分子机制。研究结果将提高CAR-T细胞在体内的持久性和治疗效果，同时为下一代CAR结构的设计提供思路，具有重大的临床转化意义。

Chimeric antigen receptor T (CAR-T) cell therapy has shown impressive clinical efficacy in patients with relapsed/refractory B cell malignancies, but the high relapse rate caused by short duration of CAR-T cells in vivo needs to be solved urgently. Our pilot results and other updated studies reveal that: the activation of IL2Rβ/IL2Rγ signaling pathway in CAR-T cells may improve its persistence in vivo, thereby reducing the relapse rate after CAR-T therapy. However, how to fine tuning of IL2Rβ/IL2Rγ signaling pathway and its mechanism of regulating CAR-T cells has not been reported yet. Based on the evidence and hypothesis, we plan to comprehensively utilize a series of technologies and platforms including extracellular vesicle (EV) based delivery system, CAR-T preparation platform and NPG tumor-bearing mouse model to conduct the following studies: develop EVs system that can deliver CD19 antigen and Neo-2/15 to anti-CD19 CAR-T cells specifically to activate its IL2Rβ/IL2Rγ pathway, and further explore the specific mechanism about how this pathway affects the proliferation and persistence of CAR-T cells. The research will extend the existence of CAR-T cells in vivo, further improve the efficacy of this therapy and provide new aspects for the design of next generation CAR structure, which has significant clinical translational significance.