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

Andrew J Hou; Ryan M Shih; Benjamin R Uy; Amanda Shafer; ZeNan L Chang; Begonya Comin-Anduix; Miriam Guemes; Zoran Galic; Su Phyu; Hideho Okada; Katie B Grausam; Joshua J Breunig; Christine E Brown; David A Nathanson; Robert M Prins; Yvonne Y Chen

doi:10.1093/neuonc/noae126

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

Neuro Oncol. 2024 Oct 3;26(10):1850-1866. doi: 10.1093/neuonc/noae126.

Authors

Andrew J Hou¹, Ryan M Shih², Benjamin R Uy³, Amanda Shafer⁴, ZeNan L Chang², Begonya Comin-Anduix^{5

6}, Miriam Guemes⁷, Zoran Galic^{6

7}, Su Phyu⁸, Hideho Okada^{8

9}, Katie B Grausam¹⁰, Joshua J Breunig¹⁰, Christine E Brown¹¹, David A Nathanson^{6

12}, Robert M Prins^{3

6

12}, Yvonne Y Chen^{1

4

6

13}

Affiliations

¹ Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA.
² Department of Molecular Biology, University of California, Los Angeles, California, USA.
³ Department of Neurosurgery, University of California, Los Angeles, California, USA.
⁴ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
⁵ Department of Surgery, University of California, Los Angeles, California, USA.
⁶ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.
⁷ Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, California, USA.
⁸ Department of Neurosurgery, University of California, San Francisco, California, USA.
⁹ Parker Institute for Cancer Immunotherapy Center at UCSF, San Francisco, California, USA.
¹⁰ Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
¹¹ Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA.
¹² Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA.
¹³ Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, California, USA.

PMID: 38982561
PMCID: PMC11449012 (available on 2025-10-03)
DOI: 10.1093/neuonc/noae126

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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MeSH terms

Animals
Brain Neoplasms* / drug therapy
Brain Neoplasms* / immunology
Brain Neoplasms* / pathology
Brain Neoplasms* / therapy
Cell Line, Tumor
Glioblastoma* / immunology
Glioblastoma* / metabolism
Glioblastoma* / pathology
Glioblastoma* / therapy
Humans
Immunotherapy, Adoptive* / methods
Interleukin-13 Receptor alpha2 Subunit* / immunology
Mice
Receptors, Chimeric Antigen* / immunology
T-Lymphocytes / immunology
Transforming Growth Factor beta* / metabolism
Tumor Cells, Cultured
Tumor Microenvironment* / immunology
Xenograft Model Antitumor Assays*

Substances

Interleukin-13 Receptor alpha2 Subunit
Receptors, Chimeric Antigen
Transforming Growth Factor beta
IL13RA2 protein, human

Abstract

MeSH terms

Substances

Grants and funding