肿瘤细胞治疗研究
英文原题：GD2-Specific CAR T Cells Demonstrate Potent and Targeted Anti-Tumor Efficacy Against Melanoma In Vitro and In Vivo.
GD2.CAR T 细胞在体外和体内均对黑色素瘤表现出强效抗肿瘤活性，凸显了其治疗潜力，值得进一步开展临床研究。
背景：二唾液酸神经节苷脂（GD2）是一种肿瘤相关抗原，在包括黑色素瘤在内的多种神经外胚层肿瘤中高表达。尽管嵌合抗原受体（CAR）T细胞免疫疗法治疗血液系统肿瘤取得显著成功，找到合适靶点仍是将该疗法拓展至实体瘤的主要障碍。 方法：使用6名健康供者的外周血T淋巴细胞，通过逆转录病毒转导制备GD2特异性CAR-T细胞。采用NanoString转录组分析、结合层次随机近邻嵌入（HSNE）降维的流式细胞术，以及针对GD2阳性和阴性黑色素瘤细胞系的体外细胞毒性实验，对GD2.CAR T细胞进行表征。还在GD2阳性异种移植模型中开展体内实验，单次瘤内注射8×10^6个GD2.CAR T细胞。 结果：GD2.CAR T细胞群以初始样表型为主（CD8+、CD40L+、CD69−、CD107a+、4-1BB+、FasL+），并通过颗粒酶A/B轴、Fas/FasL轴及细胞因子释放发挥有效抗肿瘤作用。转录组分析显示，转导相关效应影响细胞增殖；与肿瘤细胞早期共培养时，细胞向效应表型转变，同时干扰素-γ（IFN-γ）及细胞因子信号基因上调。GD2.CAR T细胞在体外对GD2阳性黑色素瘤细胞具有强细胞毒性，在异种移植模型中也能显著控制肿瘤。 结论：GD2.CAR T细胞在体内外均显示出对黑色素瘤的强效抗肿瘤活性，凸显其治疗潜力，值得进一步开展临床研究。
BACKGROUND: Disialoganglioside (GD2) is a tumor-associated antigen that is highly expressed in various neuroectodermal cancers, including melanoma. While chimeric antigen receptor (CAR) T-cell immunotherapy has demonstrated remarkable success in treating hematologic neoplasms, the identification of suitable targets remains a major obstacle in translating this approach to solid tumors. METHODS: Peripheral blood T lymphocytes from six healthy donors were used to generate GD2-specific CAR T cells via retroviral transduction. The resulting GD2.CAR T cells were characterized by NanoString transcriptome profiling, flow cytometry with hierarchical stochastic neighbor embedding (HSNE) dimensionality reduction, and in vitro cytotoxicity assays against GD2 + and GD2 - melanoma cell lines. In vivo experiments were also performed using GD2 + xenograft models and a single intratumoral dose of 8 10 6 GD2.CAR T cells. RESULT: The GD2.CAR T cell population exhibited a predominantly naive phenotype (CD8 + CD40L + CD69 CD107a + 4-1BB + FasL + ) and effective anti-tumor mechanisms involving the granzyme A/B axis, the Fas/FasL axis, and cytokine release. Transcriptome analysis revealed transduction-related effects on proliferation and a shift towards an effector phenotype during early co-culture with tumor cells, accompanied by upregulation of interferon-gamma (IFN- ) and cytokine signaling genes. GD2.CAR T cells demonstrated robust cytotoxicity against GD2 + melanoma cells in vitro , while significant in vivo tumor control was observed in xenograft models. CONCLUSION: GD2.CAR T cells demonstrate potent anti-tumor activity against melanoma in vitro and in vivo , highlighting their therapeutic potential and warranting further clinical investigation.
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