Abstract A020: TGFβRII/Switch Receptor Armoring Redirects TGFβ Signaling to Enhance EGFR CAR T Therapy in Glioblastoma

Abstract Chimeric antigen receptor (CAR) T cell–based adaptive cell therapy represents a promising strategy for glioblastoma (GBM) treatment, yet clinical efficacy remains limited due to challenges such as an immunosuppressive tumor microenvironment (TME), high tumor heterogeneity, antigen escape, and restricted penetration across the blood–brain barrier. Transforming growth factor-beta (TGFβ), secreted by tumor cells, tumor-associated macrophages (TAMs), and other cells in many solid tumors, promotes an immunosuppressive TME and hinders immune responses, including suppression of T cell function and persistence as well as cytokine production. Here, we developed a new CAR construct by armoring CAR–epidermal growth factor receptor (EGFR) with TGFβRII ectodomain/Switch Receptor (CD40, OX40, or CD27). It is concomitantly designed to eradicate tumor cells via EGFR CAR targeting and converts the inhibitory signal of TGFβ in the TME into immune-activating tumor necrosis factor receptor superfamily (TNFRSF) costimulatory signals. This dual mechanism thereby promotes T-cell survival, proliferation, and effector/memory differentiation. These engineered CAR T cells exhibited enhanced functional activity, as evidenced by increased cytokine secretion and cytotoxicity against GBM tumor cells in a repeated stimulation assay. Mechanistically, TGFβRII pull-down/co-immunoprecipitation demonstrated recruitment of TRAF family adaptors in switch receptor CAR T cells, supporting downstream TNFRSF signaling. Treatment with TGFβRII/CD40 SR, OX40 SR, or CD27 SR in the patient-derived GBM 106 tumor sphere (PBT106-TS) orthotopic model demonstrated more effective tumor growth suppression compared with the EGFR-CAR T-treated group in mice. These results support a dual-function CAR-EGFR-TGFβRII/Switch Receptor platform that couples EGFR-targeted tumor recognition with TGFβ-responsive TNFRSF costimulatory signaling, providing a strategy to counteract TGFβ-driven immune suppression in GBM. Citation Format: Jungmin Park, Nannan Li, Jesse Rodriguez, Laura Zhang, Zev Binder, Donald O'Rourke. TGFβRII/Switch Receptor Armoring Redirects TGFβ Signaling to Enhance EGFR CAR T Therapy in Glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A020.