干扰素-α调控CAR-T细胞和内源性T细胞协同抗难治复发B-ALL的免疫效应及机制研究

CD19 CAR-T细胞治疗难治复发B系急性淋巴细胞白血病（R/R B-ALL）已取得令人瞩目的成就，然而其疗效维持时间较短，复发率较高成为目前主要瓶颈。本课题组在前期临床研究中率先应用IFN-α联合CAR-T细胞治疗3例R/R ALL，发现IFN-α可促进CAR-T增殖，延长CAR-T在体内的存留时间，有助于患者获得长期分子学水平完全缓解，但具体机制尚不清楚。本课题组拟在已有的研究基础上，将通过临床试验、体外细胞实验和动物实验，应用质谱流式、单细胞测序，分子生物学等技术，阐明IFN-α增强CAR-T细胞在体内扩增、存活和杀伤功能的分子机制，并进一步揭示IFN-α和CAR-T细胞共同对内源性T细胞增效的免疫和分子机制，证实IFN-α不仅对CAR-T而且对内源性T细胞的增殖活化和功能增效均有“内外兼修”之作用，为将来设计更优化的CAR-T治疗方案，克服CAR-T后复发提供理论依据。

CD19 Chimeric antigen receptor T (CD19 CAR-T) cell therapy has achieved remarkable success in the treatment of relapse and refractory B cell acute lymphoblastic leukemia (R/R B-ALL). However, the short term remission and high recurrence rate after CAR-T therapy are still a great challenge. Our pilot study on combining interferon-α (IFN-α) and CAR-T therapy for 3 patients with R/R B-ALL indicates that IFN-α could enhance proliferation and prolong CAR-T cells persistence for long-term molecular remission. However, the detail mechanism is still unclear. Therefore, we try to conduct prospective clinical trials and preclinical studies in vivo and vitro to elucidate that IFN-α has the potential to improve CAR-T therapy and reduce relapse rate. As well as，we are going to explore the underlying immune and molecular mechanisms by some advance biology and molecular technologies such as cytometry by time-of-flight and single-cell RNA sequencing, which will confirm that IFN-α could have dual effect on promoting proliferation and enhancing immune effect of CAR-T cells and endogenous T cells. This study will help us to design optimal CAR-T treatment regimens and provide theoretical basis to overcome relapse after CAR-T.