靶向优化和信号分子修饰CAR-T细胞治疗多发性骨髓瘤及其机制研究

Multiple Myeloma (MM) is an incurable hematological malignancy. CAR-T immunotherapy for MM has shown promising outcomes in several phase I/II clinical trials; however the overall efficacy still needs to be improved. In our preliminary studies, we successfully constructed BCMA-CAR-T cells that could specifically recognize and be activated by RPMI-8226 MM cells. To further optimize and improve current CAR-T-cell therapy for MM, we propose to (1) to further optimize BCMA-CAR-T cells by specific enrichment and activation of CAR-T cells through the modification of the CAR constructs; (2) to generate novel CAR-T cells against several MM-associated antigens and antigen epitopes and to further improve the efficacy of tumor cytotoxicity by administration of a combination of CAR-T-cells with different target specificities or TanCAR-T cells; and (3) to construct novel CAR-T cells with enhanced tumor cytotoxic activity through reduced expression of the signaling scaffold molecules Gab2 and Gab3 that negatively regulate TCR signaling. Our proposed studies will further our understanding of the molecular mechanism underlying the recognition of MM-associated antigens by CAR-T cells and the activation of CAR-T cells through TCR signaling. Our proposed studies will provide novel and best strategies for dramatically improving CAR-T immunotherapy for MM.

多发性骨髓瘤（MM）是不可治愈的恶性血液肿瘤。CAR-T细胞疗法是目前最有发展前景的MM治疗方法，初步临床结果令人振奋，但其疗效仍有待提高。CAR-T细胞的优化对MM的彻底治愈意义重大。为此，我们成功构建了识别MM相关抗原BCMA的CAR-T细胞。本项目旨在进一步改良CAR-T其治疗MM的方案。1. 优化CAR结构以制备易于特异性扩增及分离的BCMA-CAR-T细胞；2. 构建针对不同MM抗原或抗原表位的CAR-T细胞及串联CAR-T细胞，研究联合CAR-T细胞治疗方案；3. 通过下调负调控TCR信号通路的细胞骨架蛋白Gab2/3在CAR-T细胞中的表达水平，构建具有更强抗肿瘤效果的新型CAR-T细胞。此研究有助于深入了解CAR-T细胞识别肿瘤抗原的机制，阐明CAR-T细胞信号传导的分子机理，为高度优化CAR-T细胞治疗MM提供新的最佳策略。

多发性骨髓瘤（MM）是不可治愈的恶性血液肿瘤。CAR-T细胞疗法是目前最有前景的MM治疗方法，但其疗效仍有待提高。CAR-T细胞的优化对MM的彻底治愈意义重大。我们已构建了具有高效MM肿瘤细胞特异性杀伤能力、易于体外特异性扩增及分离纯化的新型BCMA-CAR-T细胞。2)构建了具有MM肿瘤细胞的特异性杀伤能力的CAR-T细胞。3）开展了Gab2/3在TCR信号通路中的作用机理研究。并构建了部分针对BCMA不同抗原表位的BCMA-CAR-T细胞和识别不同MM相关抗原的载体。将进一步表达两种不同的CAR的双CAR-T细胞及识别两种不同抗原（或抗原表位）的串联CAR-T细胞，从而制定一种全新的针对不同抗原表位或不同MM表面抗原的CAR-T细胞联合治疗MM的方案；此外，通过下调CAR-T细胞中的Gab2/3 的表达水平，构建具有更强抗肿瘤功效果的新型BCMA-CAR-T细胞的工作还在进行之中。此研究有助于深入了解CAR-T细胞识别肿瘤抗原的机制，阐明CAR-T细胞信号传导的分子机理，为高度优化CAR-T细胞治疗MM提供新的最佳策略。