{Reference Type}: Journal Article
{Title}: IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses in glioblastoma.
{Author}: Hou AJ;Shih RM;Uy BR;Shafer A;Chang ZNL;Comin-Anduix B;Guemes M;Galic Z;Phyu S;Okada H;Grausam KB;Breunig JJ;Brown CE;Nathanson DA;Prins RM;Chen YY;
{Journal}: Neuro Oncol
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jul 10
{Factor}: 13.029
{DOI}: 10.1093/neuonc/noae126
{Abstract}: <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.