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Updated: Jun 21, 2025

Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care

Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care

Published on: February 16, 2015

IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses

Andrew J Hou¹, Ryan M Shih², Benjamin R Uy³

¹Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA.

|July 10, 2024

Abstract

Background:

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.

Methods:

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.

Results:

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.

Conclusions:

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.

Keywords:

CAR-T cell therapy TGF-β glioblastoma immunotherapy tumor microenvironment

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