Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells used to eliminate tumor cells. The human transforming growth factor β (TGF-β) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. To mitigate TGF-β-mediated suppressive activity, we combined a dominant-negative TGF-β receptor II (dnTGFβRII) with our previous bicistronic CART-EGFR-IL13Rα2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13Rα2-dnTGFβRII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggest that CART-EGFR-IL13Rα2-dnTGFβRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. In addition, studies validate the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.

中文翻译：

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具有显性失活 TGF-β 受体 II 的装甲双顺反子 CAR T 细胞可克服胶质母细胞瘤的耐药性


嵌合抗原受体（CAR）T细胞在血液疾病方面显示出显着疗效。然而，CAR T 疗法在实体瘤（包括胶质母细胞瘤（GBM））中的疗效有限。最重要的原因之一是免疫抑制性肿瘤微环境（TME），它促进肿瘤生长并抑制用于消除肿瘤细胞的免疫细胞。人类转化生长因子 β (TGF-β) 在形成抑制性 GBM TME 和驱动抗 GBM 反应的抑制中发挥着至关重要的作用。为了减轻 TGF-β 介导的抑制活性，我们将显性失活 TGF-β 受体 II (dnTGFβRII) 与我们之前的双顺反子 CART-EGFR-IL13Rα2 构建体（目前正在临床试验中进行评估）相结合，以生成 CART-EGFR-IL13Rα2 -dnTGFβRII，我们正在开发用于临床应用的三模块结构。我们假设这种方法将更有效地颠覆 GBM 观察到的耐药机制。我们的数据表明，CART-EGFR-IL13Rα2-dnTGFβRII 显着增强 T 细胞增殖，增强功能反应，并改善旁观细胞的适应性，特别是通过降低富含 TGF-β 的 TME 中的 TGF-β 浓度。此外，研究还验证了 dnTGFβRII 与 CAR 配合在 NSG 小鼠模型中靶向和根除 GBM 的安全性和有效性。