Abstract：
BACKGROUND: 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.
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.
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.
摘要：
背景：针对胶质母细胞瘤（GBM）相关抗原如白细胞介素-13受体亚基α-2（IL-13Rα2）的嵌合抗原受体（CAR）-T细胞疗法迄今取得了有限的临床疗效，部分是由于以抑制分子如转化生长因子-β(TGF-β)为特征的免疫抑制肿瘤微环境(TME)。这项研究的目的是通过在TME中对抗TGF-β介导的免疫抑制来设计更有效的靶向GBM的CAR-T细胞。
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。
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。
