CELL INTELLIGENCE · 肿瘤细胞治疗研究

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 (TGF- ) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. To mitigate TGF- -mediated suppressive activity, we combined a dominant-negative TGF- receptor II (dnTGF RII) with our previous bicistronic CART-EGFR-IL13R 2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13R 2-dnTGF RII, 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-IL13R 2-dnTGF RII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF- concentration in a TGF- -rich TME. In addition, in vivo studies validate the safety and efficacy of the dnTGF RII cooperating with CARs in targeting and eradicating GBM in an NSG mouse model.