在 GD2 阳性转移性黑色素瘤和其他实体瘤患者中进行的 GD2 特异性 CAR-T 细胞的 1 期试验的安全性和生物学结果。

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions. METHODS: We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed. RESULTS: We demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy. CONCLUSIONS: This is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect. TRIAL REGISTRATION NUMBER: ACTRN12613000198729.

背景：针对 CD19 和 B 细胞成熟抗原的嵌合抗原受体 (CAR) T 细胞疗法已成为全球复发和难治性 B 细胞恶性肿瘤的标准治疗方法。如果要将 CAR-T 细胞疗法用于非血液系统恶性肿瘤，则需要进行迭代的早期临床试验，从而为评估不同 CAR 设计和不同制造条件下的 CAR-T 细胞产品的临床开发过程增加价值。

方法：我们进行了一项针对第三代 GD2 特异性 CAR-T 细胞疗法的 1 期试验，该疗法此前已在神经母细胞瘤患者中进行了测试。在这项研究中，GD2-CAR-T 疗法首次在转移性黑色素瘤患者中与 BRAF/MEK 抑制剂联合治疗进行了评估，并在结直肠癌患者和纤维粘液肉瘤患者中进行了单药治疗。我们确定了可行性和安全性，并进行了持久性研究、血清中的多重细胞因子阵列以及对原始 CAR-T 产品、循环 CAR-T 细胞的详细免疫表型分析，在一些选定的患者中还分析了肿瘤浸润性 CAR-T 细胞。

结果：我们证明了为患有实体瘤的患者在治疗点制造 CAR-T 产品的可行性，并表明单次静脉输注可耐受良好，没有剂量限制毒性或严重的不良事件。此外，我们注意到，当对后 6 名入组该 12 名患者试验的患者采用改良的制造程序时，CAR-T 细胞免疫表型和扩增均有显著改善。我们还证明了 CAR-T 细胞介导的免疫活性的证据，并且在 CAR-T 细胞治疗后，一些患者的循环髓样细胞亚群有所扩增。

结论：这是第三代靶向 GD2 的 CAR-T 细胞在转移性黑色素瘤和其他实体瘤（如结直肠癌）患者中的首次报告，显示了可行性、安全性和免疫活性，但临床效果有限。

试验注册号：ACTRN12613000198729。