肿瘤细胞治疗研究
英文原题：CAR-γδ T Cells Targeting Claudin18.2 Show Superior Cytotoxicity Against Solid Tumor Compared to Traditional CAR-αβ T Cells.
我们的结果表明，通用型 CAR-CLDN18.2- T 细胞有望用于治疗 CLDN18.2 阳性实体瘤，并为开发更通用的 CAR-T 细胞肿瘤免疫治疗策略提供了启示。
背景：Claudin 18.2（CLDN18.2）在多种恶性肿瘤发生过程中高表达，尤其是胃癌，靶向 CLDN18.2 的 CAR-T 细胞具有治疗潜力。然而，这些细胞依赖主要组织相容性复合体（MHC）识别抗原，限制了应用。人 γδ T 细胞对多数实体瘤具有强效 MHC 非依赖性细胞毒性，无论体内还是体外均如此，因此正在成为制备强效通用 CLDN18.2 CAR-T、治疗实体瘤的理想细胞。本研究旨在构建靶向 CLDN18.2 的通用 CAR-γδ T 细胞。方法：研究者通过慢病毒感染构建新型 CAR-CLDN18.2-γδ T 细胞，并比较其在体内外治疗 CLDN18.2 阳性实体瘤的疗效。结果：慢病毒转染 CLDN18.2 CAR 后，在 HEK293T 细胞中验证了 CD3 表达；慢病毒经包装和浓缩后滴度为 4.90 × 10⁸ TU/mL。原代 T 细胞和 γδ T 细胞感染效率分别约为 31.76 ± 4.122% 和 44.13 ± 4.436%。CAR-CLDN18.2-γδ T 细胞对 CLDN18.2 阳性胃癌细胞表现出特异性细胞毒性，并分泌相对较高水平的颗粒酶 B、穿孔素-1 和 IFN-γ。体外实验中，CAR-γδ T 细胞对靶细胞的细胞毒性也优于经典 CAR-γδ T 细胞。最后，在负载肿瘤的 NSG 小鼠中评估 T-CAR-CLDN18.2 细胞的抗肿瘤活性；CAR-CLDN18.2-γδ T 细胞显著抑制肿瘤生长并延长小鼠生存。结论：结果显示，通用 CAR-CLDN18.2-γδ T 细胞有望用于治疗 CLDN18.2 阳性实体瘤，并为开发更通用的肿瘤免疫治疗 CAR-γδ T 细胞策略提供见解。
BACKGROUND: Claudin18.2 (CLDN18.2) is highly expressed during the development of various malignant tumors, especially gastric cancer, and CAR-T cells targeting CLDN18.2 have therapeutic potential. However, their dependence on the major histocompatibility complex (MHC) for antigen recognition limits their application. Human Gamma Delta ( ) T cells, with strong MHC-independent cytotoxicity to most solid tumors both in vivo and in vitro, are emerging as ideal cells for the generation of robust universal CLDN18.2 CAR-T cells to treat solid tumors. Our aim was to construct a universal CAR- T cell targeting CLDN18.2. METHODS: We constructed novel CAR-CLDN18.2- T cells by lentiviral infection and compared their superior efficacy in the treatment of CLDN18.2-positive solid tumors in vivo and in vitro. RESULTS: CD3 expression was verified in HEK293T cells after lentiviral transfection of CLDN18.2 CAR, and the lentivirus was packaged and concentrated to a titer of 4.90 10 8 TU/mL. Primary T cells and T cells were infected with efficiencies of approximately 31.76 4.122% and 44.13 4.436%, respectively. CAR-CLDN18.2- T cells exhibited specific cytotoxicity against CLDN18.2-positive gastric cancer cells and secreted relatively high levels of Granzyme-B, Perforin-1, and IFN- . CAR- T cells also showed superior cytotoxicity to target cells compared to classical CAR- T cells in vitro. Finally, the antitumor activity of T-CAR-CLDN18.2 cells was evaluated in tumor-bearing NSG mice, and CAR-CLDN18.2- T cells significantly inhibited tumor growth and prolonged the survival of the mice. CONCLUSIONS: Our results demonstrate that universal CAR-CLDN18.2- T cell is promising for the treatment of CLDN18.2-positive solid tumor and provide insights for the development of more universal CAR- T-cell strategies for tumor immunotherapy.
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