BCMA-CAR-T细胞治疗多发性骨髓瘤后出现复发进展的免疫逃逸机制研究

靶向BCMA的CAR-T细胞（BCMA-CAR-T）在治疗复发难治性多发性骨髓瘤（MM）临床试验中疗效突出，被认为是可以取代传统化疗和骨髓移植的新型肿瘤免疫疗法。但从我们前期的临床试验数据来看，BCMA-CAR-T的疗效存在显著的个体差异，即部分患者获得了良好而持久的治疗反应，而部分患者仍会出现疾病的复发进展，这其中是否存在免疫逃逸机制，是一个亟待解决的重要问题。本项目以BCMA-CAR-T治疗MM后出现复发进展为研究立足点，探讨CAR-T细胞的活性缺陷机制、骨髓瘤细胞的治疗抵抗机制，从深层次解析BCMA-CAR-T治疗后疾病复发进展的潜在原因，为改进CAR-T细胞制备和疾病评估手段提供充分的证据，并在此基础上，从免疫调节的角度进一步探索CAR-T细胞联合用药的作用机制，以期优化CAR-T治疗方案，为提高BCMA-CAR-T细胞的临床疗效，丰富和完善MM的免疫治疗策略奠定理论基础。

BCMA-directed CAR-T cells is a promising treatment for relapsed/refractory multiple myeloma (MM). This effective approach is considered to be an alternative to conventional chemotherapy and bone marrow transplantation, and expected to achieve a complete cure of MM. However, our previous data indicated that the efficacy of CAR-T therapy was different among cases. Some patients have good and long-lasting response, while some patients still got MM relapse/progression. Whether immune escape mechanisms involve in the relapsed/progressed cases is an important issue, and requiring further research. Therefore, this project focuses on the MM relapse/progression after CAR-T, exploring the underlying immunodeficiency mechanism of CAR-T cells, and the therapeutic resistance mechanism of MM cells, so as to analyze the causes of relapse/progression, and to provide theoretical basis for improving the laboratory preparation of BCMA-CAR-T cells, as well as improving the monitoring and evaluation of MM diseases before and after CAR-T. Meanwhile, we apply BCMA-CAR-T combined with other immunomodulatory drugs to study the response and effect, and explore their mechanisms in order to optimize the CAR-T treatment scheme, enrich and improve the immunotherapy strategy for MM.