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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02875-1

摘要内容如下：

嵌合抗原受体T细胞（CAR-T）疗法是一种新兴的策略，用于改善复发性高级别胶质瘤的治疗结果，这种癌症对目前的治疗方法反应不佳。在此，我们报道了一项完整的I期试验，该试验评估了65例复发性高级别胶质瘤患者的IL-13Rα2靶向CAR-T细胞，其中大多数为复发性胶质母细胞瘤（RGBM）。主要目标是安全性和可行性、最大耐受剂量/最大可行剂量和推荐的2期剂量计划。次要目标包括总生存率、疾病反应、细胞因子动力学和肿瘤免疫环境生物标志物。该试验旨在评估局部区域T细胞给药的三种途径（肿瘤内（ICT）、脑室内（ICV）和双ICT/ICV）和两个生产平台，最终在第5组中采用双ICT/ICV给药和优化的生产工艺。局部区域CAR-T细胞给药是可行的，且耐受性良好，由于所有组均无剂量限制性毒性，因此未确定最大耐受剂量。可能与治疗相关的3+级毒性为1例3级脑病和1例3级共济失调。第5组的临床最大可行剂量为每输注周期200×106个CAR-T细胞；然而，由于制造的可行性，其他武器要么没有测试，要么没有达到这个剂量。推荐的2期剂量将在未来的研究中根据该试验的数据进行调整。50%（29/58）的患者病情稳定或更好，两次部分缓解，一次完全缓解，在额外的CAR-T周期后第二次完全缓解。对于RGBM，所有患者的中位总生存期为7.7个月，第5组为10.2个月。中枢神经系统炎性细胞因子（包括IFNγ、CXCL9和CXCL10）的增加与CAR-T细胞给药和生物活性相关。治疗前肿瘤内CD3T细胞水平与生存率呈正相关。这些发现表明，局部区域IL-13Rα2靶向的CAR-T疗法是安全的，在一部分患者中具有良好的临床活性。ClinicalTrials.gov标识符：NCT02208362。

英文原文如下：

Abstracts

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

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