细胞膜修饰策略在广谱新抗原特异性TCR-T细胞治疗新模式中的应用与评价

新抗原特异性TCR-T细胞治疗是肿瘤治疗中最具潜力的免疫治疗新策略之一，但包括胃癌在内的实体肿瘤存在自身免疫原性弱、新抗原高度异质性并缺乏高频新抗原等特点；也存在免疫细胞难以有效穿透并聚集在实体肿瘤组织深部、肿瘤微环境具有免疫抑制性等免疫细胞发挥效应的共性问题。本课题在申请人前期研究基础上，以细胞膜修饰为策略提出克服上述限制因素的方法：一方面对肿瘤细胞进行细胞膜修饰，在肿瘤细胞膜表面加载TCR-T细胞识别靶点和PD-1阻断性抗体片段，使TCR-T细胞能够更加高效识别肿瘤细胞并且进行有效杀伤；另一方面对TCR-T进行细胞膜修饰，将肿瘤穿透肽加载到T细胞膜表面，增加TCR-T细胞在肿瘤组织的聚集。本项目运用细胞膜修饰技术建立的广谱高穿透型新抗原特异性TCR-T细胞治疗模式将从一个新角度拓宽实体瘤TCR-T技术的视野，为提高实体瘤新抗原特异性TCR-T细胞治疗的普适性和治疗疗效提供了科学依据。

Neoantigen-specific TCR-T cell therapy is one of the most potential immunotherapy strategies in cancer treatment. However, there are several major obstacles in clinical settings of solid tumors such as gastric cancer: lacking of universal targets for T cell recognition on tumor cell surface, failure of penetrating of T cells to the center of solid tumor and immunosuppressive tumor microenvironment. Our previous researches proposed a strategy of cell membrane modification to overcome the above three limitations. The tumor cell membrane is modified by loaded TCR-T cell recognition targets and PD-1 blocking antibody fragments, so that TCR-T cells can recognize the tumor cells and kill them effectively. On the other hand, tumor-penetrating peptide was loaded onto the surface of T cell membrane to increase the accumulation of engineered T cells in tumor tissues. This broad-spectrum and high-penetrating neoantigen-specific TCR-T cell therapy model established by cell membrane modification technology will broaden the application of TCR-T technology in solid tumor treatment. It will provide a scientific strategy for improving the universality and therapeutic efficacy of neoantigen-specific TCR-T cell therapy.