针对胶质母细胞瘤 (GBM) 相关抗原（例如白细胞介素 13 受体亚基 α-2 (IL-13Rα2)）的嵌合抗原受体 (CAR)-T 细胞疗法迄今为止取得的临床疗效有限，部分原因是免疫抑制的肿瘤微环境。 TME）以抑制性分子为特征，例如转化生长因子-β (TGF-β)。本研究的目的是通过对抗 TME 中 TGF-β 介导的免疫抑制来设计更有效的 GBM 靶向 CAR-T 细胞。我们设计了一种针对 IL-13Rα2 和 TGF-β 的单链双特异性 CAR，肿瘤特异性 T 细胞将 TGF-β 从免疫抑制剂转化为免疫刺激剂。评估了双特异性 IL-13Rα2/TGF-β CAR-T 细胞对患者来源的 GBM 异种移植物和小鼠神经胶质瘤同基因模型的有效性和安全性。使用 IL-13Rα2/TGF-β CAR-T 细胞治疗可产生更大的 T-与传统的 IL-13Rα2 CAR-T 细胞治疗相比，荷瘤大脑中细胞浸润和减少的抑制性骨髓细胞存在，从而提高了患者来源的 GBM 异种移植物和小鼠神经胶质瘤同基因模型的存活率。我们的研究结果表明，通过重编程肿瘤特异性 T 细胞对 TGF-β 的反应，双特异性 IL-13Rα2/TGF-β CAR-T 细胞抵抗并重塑免疫抑制 TME，以驱动 GBM 中的有效抗肿瘤反应。© 作者 2024。已发表由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限都可以通过我们网站文章页面上的权限链接通过我们的 RightsLink 服务获得 - 如需了解更多信息，请联系journals.permissions@oup.com。

Chimeric antigen receptor (CAR)-T cell therapies targeting glioblastoma (GBM)-associated antigens such as interleukin-13 receptor subunit alpha-2 (IL-13Rα2) have achieved limited clinical efficacy to date, in part due to an immunosuppressive tumor microenvironment (TME) characterized by inhibitory molecules such as transforming growth factor-beta (TGF-β). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-β-mediated immune suppression in the TME.We engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-β, which programs tumor-specific T cells to convert TGF-β from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-β CAR-T cells were evaluated for efficacy and safety against both patient-derived GBM xenografts and syngeneic models of murine glioma.Treatment with IL-13Rα2/TGF-β CAR-T cells leads to greater T-cell infiltration and reduced suppressive myeloid cell presence in the tumor-bearing brain compared to treatment with conventional IL-13Rα2 CAR-T cells, resulting in improved survival in both patient-derived GBM xenografts and syngeneic models of murine glioma.Our findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-β, bispecific IL-13Rα2/TGF-β CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.