%0 Journal Article
%T IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses in glioblastoma.
%A Hou AJ
%A Shih RM
%A Uy BR
%A Shafer A
%A Chang ZNL
%A Comin-Anduix B
%A Guemes M
%A Galic Z
%A Phyu S
%A Okada H
%A Grausam KB
%A Breunig JJ
%A Brown CE
%A Nathanson DA
%A Prins RM
%A Chen YY
%J Neuro Oncol
%V 0
%N 0
%D 2024 Jul 10
%M 38982561
%F 13.029
%R 10.1093/neuonc/noae126
%X <B>BACKGROUND: </B>Chimeric antigen receptor (CAR)-T cell therapies targeting glioblastoma (GBM)-associated antigens such as interleukin-13 receptor subunit alpha-2 (IL-13Rα2) have achieved limited clinical efficacy to date, in part due to an immunosuppressive tumor microenvironment (TME) characterized by inhibitory molecules such as transforming growth factor-beta (TGF-β). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-β-mediated immune suppression in the TME.<BR><B>METHODS: </B>We engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-β, which programs tumor-specific T cells to convert TGF-β from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-β CAR-T cells were evaluated for efficacy and safety against both patient-derived GBM xenografts and syngeneic models of murine glioma.<BR><B>RESULTS: </B>Treatment with IL-13Rα2/TGF-β CAR-T cells leads to greater T-cell infiltration and reduced suppressive myeloid cell presence in the tumor-bearing brain compared to treatment with conventional IL-13Rα2 CAR-T cells, resulting in improved survival in both patient-derived GBM xenografts and syngeneic models of murine glioma.<BR><B>CONCLUSIONS: </B>Our findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-β, bispecific IL-13Rα2/TGF-β CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.