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

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.

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。

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。为了进一步提高其持久疗效，本项目创新性将C5aR活性结构域引入CAR作为共刺激分子，构建了新型BB-ζ-C5aR CAR-T细胞，获得了发明专利，并分别针对表达CD19+和BCMA+的B细胞白血病和多发性骨髓瘤开展了系统性基础和临床转化研究。我们在体外和体内建立了多种白血病和多发性骨髓瘤的细胞和小鼠模型，明确了BB-ζ-C5aR CAR-T细胞的肿瘤杀伤效应和持久性显著提高，具有良好的临床转化潜能。并揭示了C5aR结构域的整合促进了CAR-T表现为具有肿瘤杀伤能力的Th17细胞表型，而抑制Treg表型，并且形成较多的记忆性T细胞，从而发挥有效而持久的肿瘤杀伤功能的机制。最后成功开展了BB-ζ-C5aR CAR-T细胞治疗复发难治性白血病患者的临床试验，结果显示新型CAR-T细胞治疗的患者获得了完全缓解，临床不良反应可控，展现了BB-ζ-C5aR CAR-T细胞治疗的有效性和安全性。本项目的研究成果拓展了CAR分子设计的新思路，推进新型CAR-T细胞在复发难治性白血病中的应用，提升其治疗效果，助力CAR-T疗效提升与应用领域升级。