异体干细胞工程化 EGFRvIII 特异性 CAR-NKT 细胞治疗胶质母细胞瘤，疗效和安全性增强

英文原题：Allogeneic stem cell-engineered EGFRvIII-specific CAR-NKT cells for treating glioblastoma with enhanced efficacy and safety.

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Allogeneic stem cell-engineered EGFRvIII-specific CAR-NKT cells for treating glioblastoma with enhanced efficacy and safety.

PubMed 2025/09/12（内容时间） Mol Ther Q1 · IF 11.4（JCR 2025）

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人群：成人靶点：EGFRvIII 技术：CAR-T 技术：NK 细胞胶质母细胞瘤脑肿瘤

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研究概要

我们的这些发现共同支持 Allo ECAR-NKT 细胞作为一种下一代、现货型免疫疗法，用于治疗 GBM 时具有更强的疗效和安全性。

中文摘要

胶质母细胞瘤（GBM）是成人中侵袭性最强、致死率最高的原发性脑肿瘤，对包括手术切除、放射治疗、化疗和靶向药物在内的标准疗法均有耐药。尽管嵌合抗原受体（CAR）工程化T（CAR-T）细胞疗法已成为有前景的GBM免疫治疗方法，其应用仍受肿瘤抗原逃逸、免疫抑制性肿瘤微环境（TME）、细胞因子释放综合征（CRS）等治疗相关毒性，以及自体细胞制备流程复杂等因素限制。在本研究中，我们结合造血干细胞和祖细胞（HSPC）基因工程改造及无饲养细胞体外分化方案，通过具备临床转化设计且可规模化的平台，制备了靶向EGFRvIII的异基因CAR工程化不变型自然杀伤T（Allo ECAR-NKT）细胞。这些细胞对GBM表现出强效、多层面的抗肿瘤活性，包括通过CAR和NK受体直接杀伤肿瘤细胞，以及通过其不变型T细胞受体选择性靶向TME中的CD1d+免疫抑制细胞。在皮下和原位GBM人源化模型中，Allo ECAR-NKT细胞均显示出强效疗效、极少从脑部向全身泄漏，且CRS风险较低。综上，我们的发现支持Allo ECAR-NKT细胞作为治疗GBM的下一代现货型免疫疗法，具有更高疗效和安全性。

展开英文摘要原文

Glioblastoma (GBM) is the most aggressive and lethal primary brain tumor in adults, characterized by resistance to standard therapies, including surgical resection, radiation, chemotherapy, and targeted agents. While chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has emerged as a promising immunotherapeutic approach for GBM, its application remains limited by tumor antigen escape, an immunosuppressive tumor microenvironment (TME), treatment-associated toxicities such as cytokine release syndrome (CRS), and the logistical complexities of autologous cell manufacturing. In this study, we leveraged hematopoietic stem and progenitor cell (HSPC) gene engineering combined with a feeder-free, ex vivo differentiation protocol to generate allogeneic EGFRvIII-specific CAR-engineered invariant natural killer T ( Allo ECAR-NKT) cells through a clinically guided, scalable platform. These cells exhibit potent, multifaceted antitumor activity against GBM, including direct tumor cell killing via CAR and NK receptors and selective targeting of CD1d + immunosuppressive cells within the TME via their invariant T cell receptors. In both subcutaneous and orthotopic GBM humanized models, Allo ECAR-NKT cells demonstrated robust efficacy, minimal systemic leakage from the brain, and a reduced risk of CRS. Collectively, our findings support Allo ECAR-NKT cells as a next-generation, off-the-shelf immunotherapy with enhanced efficacy and safety for the treatment of GBM.

论文信息

作者: Li YR、Zhu Y、Li Z、Shen X、Halladay T、Tse C、Tian Y、Huang J
第一作者单位: Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: charlie.li@ucla.edu.United States
通讯作者单位: Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.United States
期刊: Molecular therapy : the journal of the American Society of Gene Therapy2025 Dec 3

原文标识: PubMed 40946163　·　DOI 10.1016/j.ymthe.2025.09.026

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