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

Autor:	Hou AJ; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA., Shih RM; Department of Molecular Biology, University of California, Los Angeles, California, USA., Uy BR; Department of Neurosurgery, University of California, Los Angeles, California, USA., Shafer A; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA., Chang ZL; Department of Molecular Biology, University of California, Los Angeles, California, USA., Comin-Anduix B; Department of Surgery, University of California, Los Angeles, California, USA.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA., Guemes M; Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, California, USA., Galic Z; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.; Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, California, USA., Phyu S; Department of Neurosurgery, University of California, San Francisco, California, USA., Okada H; Department of Neurosurgery, University of California, San Francisco, California, USA.; Parker Institute for Cancer Immunotherapy Center at UCSF, San Francisco, California, USA., Grausam KB; Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA., Breunig JJ; Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA., Brown CE; Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center and Beckman Research Institute, Duarte, California, USA., Nathanson DA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA., Prins RM; Department of Neurosurgery, University of California, Los Angeles, California, USA.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA., Chen YY; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California, USA.; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA.; Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, California, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Oct 03; Vol. 26 (10), pp. 1850-1866.
DOI:	10.1093/neuonc/noae126
Abstrakt:	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. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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