Department of Neurosurgery, First Affiliated Hospital of Harbin Medical University, Harbin 150001, China; Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Neurosurgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Mol Ther. 2024 Oct 2;32(10):3522-3538. doi: 10.1016/j.ymthe.2024.07.020. Epub 2024 Jul 31.
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, in vivo studies validate the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.
嵌合抗原受体 (CAR) T 细胞在血液系统疾病中显示出显著的疗效。然而，CAR T 疗法在实体瘤中，包括胶质母细胞瘤（GBM），疗效有限。其中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 和驱动抑制抗 GBM 反应方面起着至关重要的作用。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 构建体结合，该构建体目前正在临床试验中进行评估，以生成 CART-EGFR-IL13Rα2-dnTGFβRII，这是我们正在开发用于临床应用的三模块构建体。我们假设这种方法将更有效地克服与 GBM 观察到的耐药机制。我们的数据表明，CART-EGFR-IL13Rα2-dnTGFβRII 可显著增强 T 细胞增殖，增强功能反应，并改善旁观者细胞的适应性，特别是通过降低 TGF-β 浓度在 TGF-β 丰富的 TME 中。此外，体内研究验证了 dnTGFβRII 与 CAR 合作靶向和消除 NSG 小鼠模型中 GBM 的安全性和有效性。
