以C5aR为新型胞内共刺激分子增强CAR-T抗白血病的基础与临床研究

嵌合抗原受体T细胞（CAR-T）疗法是肿瘤免疫治疗发展的里程碑，但仍需改进以更安全有效地治疗白血病。我们前期发现对CAR-T应答良好的患者C5aR及Th17相关基因表达水平显著升高；并且发现C5aR活化可促进T细胞增殖分化为具有肿瘤杀伤潜能的Th17细胞。由此，提出将C5aR引入作为CAR的新型共刺激分子结构域，可上调Th17亚群增强CAR-T的肿瘤杀伤能力，提高其治疗白血病的有效性的科学假说。本项目已构建新型BB-ζ-C5aR CAR-T、并申请PCT专利，拟应用原代、白血病细胞系及人源化白血病小鼠模型，研究新型CAR-T的肿瘤杀伤能力；应用单细胞转录组测序等技术在细胞和分子水平上揭示C5aR信号增强CAR-T肿瘤杀伤能力的机制；最后在临床试验中明确BB-ζ-C5aR CAR-T治疗复发难治性白血病的安全性和有效性。研究成果不仅有望用于白血病的治疗，也将极大推动CAR-T设计研究和应用。

Chimeric antigen receptor (CAR)-modified adoptive T-cell therapy is a promising new approach in cancer immunotherapy, and new strategies to improve its anti-tumor efficacy and safety are undergoing. Our previous studies have revealed that the B-cell acute lymphoblastic leukemia patients obtained complete remission (CR) exhibited an elevation of C5aR expression. In addition, we found C5aR activation promoted the differentiation of Th17 cells, a critical T subset required for cancer immontherapy. Based on our previous work, we hypothesize that “C5aR incorporation would augment CAR T-cell activity against tumors through Th17 cells expansion”. In this study, we have generated a novel CAR-T cells, namely BB-ζ-C5aR CAR T, and applied for patents. We next plan to use in vitro and in vivo models to investigate the potential antitumor effect of BB-ζ-C5aR CAR T and the molecular mechanisms involved. Of note, we would design a clinical trial and carry out it for treating patients with refractory and/or relapse lymphoblastic leukemia. The outcome of this study will contribute to promotion of CAR design and the development of new therapeutic strategy for refractory and/or relapse lymphoblastic leukemia even for solid tumor in the future.