肿瘤细胞治疗研究
英文原题：Construction of Switch Modules for CAR-T Cell Treatment Using a Site-Specific Conjugation System.
CAR-T 细胞（CAR-T 细胞）疗法已成为 B 细胞血液肿瘤一种有前景的治疗选择。
CAR-T 细胞疗法已成为治疗 B 细胞血液肿瘤的有前景选择，但可选靶抗原有限，且靶抗原丢失所致的疾病复发限制了 CAR-T 的广泛临床应用。本研究使用位点特异性偶联系统，将由抗体（Ab）结构域和 SpyCatcher 结构域组成的抗体融合蛋白与 FITC-SpyTag（FITC-ST）肽偶联，构建双特异性安全开关模块。研究分别制备 FMC63（抗 CD19）、anti-PDL1 和 ZHER（抗 HER2）-FITC-ST 开关模块，以靶向表达 CD19、PD-L1 或 HER2 的肿瘤细胞。这些开关模块显著增强抗 FITC CAR-T 细胞对肿瘤细胞的细胞毒作用。此外，研究通过优化较短版本的 CD8 结合适配体，获得纯化 CD8+ T 细胞并制备抗 FITC CD8-CAR-T 细胞；该细胞与抗 CD4 的 CD4-FITC-ST 开关模块联合使用，可在体外和体内清除 CD4 阳性肿瘤细胞。总之，研究通过位点特异性偶联建立了一种新型安全开关模块，可增强通用 CAR-T 的抗肿瘤功能，扩大 CAR-T 疗法应用范围并提高其安全性和疗效。
Chimeric antigen receptor T-cell (CAR-T cell) therapy has become a promising treatment option for B-cell hematological tumors. However, few optional target antigens and disease relapse due to loss of target antigens limit the broad clinical applicability of CAR-T cells. Here, we conjugated an antibody (Ab) fusion protein, consisting of an Ab domain and a SpyCatcher domain, with the FITC-SpyTag (FITC-ST) peptide to form a bispecific safety switch module using a site-specific conjugation system. We applied the safety switch module to target CD19, PDL1, or Her2-expressing tumor cells by constructing FMC63 (anti-CD19), antiPDL1, or ZHER (anti-Her2)-FITC-ST, respectively. Those switch modules significantly improved the cytotoxic effects of anti-FITC CAR-T cells on tumor cells. Additionally, we obtained the purified CD8 + T cells by optimizing a shorter version of the CD8-binding aptamer to generate anti-FITC CD8-CAR-T cells, which combined with the CD4-FITC-ST switch module (anti-CD4) to eliminate the CD4-positive tumor cells in vitro and in vivo. Overall, we established a novel safety switch module by site-specific conjugation to enhance the antitumor function of universal CAR-T cells, thereby expanding the application scope of CAR-T therapy and improving its safety and efficacy.
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