METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
方法:我们设计了一个单链,靶向IL-13Rα2和TGF-β的双特异性CAR,对肿瘤特异性T细胞进行编程以将TGF-β从免疫抑制剂转化为免疫刺激剂。评估双特异性IL-13Rα2/TGF-βCAR-T细胞针对患者来源的GBM异种移植物和鼠神经胶质瘤的同基因模型的功效和安全性。
结果:与常规IL-13Rα2CAR-T细胞治疗相比,IL-13Rα2/TGF-βCAR-T细胞治疗导致荷瘤脑中更大的T细胞浸润和减少抑制性骨髓细胞存在,导致患者来源的GBM异种移植物和小鼠神经胶质瘤同基因模型的存活率都得到改善。
结论:我们的研究结果表明,通过重新编程肿瘤特异性T细胞对TGF-β的反应,双特异性IL-13Rα2/TGF-βCAR-T细胞抵抗并重塑免疫抑制性TME以驱动GBM中的有效抗肿瘤反应。