Armored Bicistronic CAR T Cells with Dominant-negative TGF-β Receptor II to Overcome Resistance in Glioblastoma

Abstract

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 to eliminate tumor cells. The human transforming growth factor-beta (TGF-β) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. In order 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. Additionally, in vivo studies validated the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in a NSG mouse model.