Intrathecal CRISPR-edited allogeneic IL-13Rα2 CAR T Cells for recurrent high-grade Glioma: preclinical characterization and phase I trial

作者：X. Li, Xiaoyun Shang, Jiangang Liu, Yang Zhang, Xian Jia, H. Li, Yihan Wang, Jianen Gao, Xu Ma, X H Zhang, Xiaoci Rong, Wen-Juan Gan, Yu Zhang, Jie Chen, Lin Wang, Zhen Bao, Liang He, Xigang Yan, Yang Liu, Jie Shao, Zongyu Xiao, Zhiming Wang, Zhiming Wang, Haiping Zhu, Zhong Wang, Zhong Wang, Yuzhang Wu, Yulun Huang · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-025-68112-6 · 被引用次数：7 · 研究领域：CAR-T cell therapy research、CRISPR and Genetic Engineering、Virus-based gene therapy research

Patients with recurrent high-grade glioblastoma have a median survival of 6-8 months, with limited therapeutic options. In recent years, interest has grown in applying chimeric antigen receptor T (CAR-T) cells to solid cancers, including advanced gliomas. Here we generated off-the-shelf CRISPR-Cas9–edited IL-13Rα2-specific allogeneic universal CAR-T cells (MT026) by disrupting the endogenous TCR to prevent graft-versus-host disease and knocking out HLA class I molecules to mitigate the host-versus-graft response, and observed minimal NK-cell–mediated rejection in preclinical studies. In a first-in-human, single-center, open-label investigator-initiated trial (ChiCTR2000028801) in patients with high-grade glioma with prior therapy failure and short life expectancy, intrathecal injection of MT026 via lumbar puncture (1.0-3.0×10^7 cells per dose) demonstrated favorable tolerability and safety (primary outcome), pharmacokinetic characteristics, and preliminary clinical activity (secondary outcomes). Among the five patients enrolled, one achieved a complete response and three achieved partial responses. No grade ≥3 adverse events were observed; the predominant treatment-related toxicities were grade 1-2 pyrexia, hypoxia, and vomiting. Trial enrolment was halted after enrolment of the first five patients, however these preliminary clinical data support the potential benefit of locally administered allogeneic universal CAR-T cell therapy for recurrent glioblastoma. Off-the-shelf, on...