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IL-13Rα2/TGF-ß bispecific CAR-T cells counter TGF-ß-mediated immune suppression and potentiate anti-tumor responses in glioblastoma.
Hou, Andrew J; Shih, Ryan M; Uy, Benjamin R; Shafer, Amanda; Chang, Ze Nan L; Comin-Anduix, Begonya; Guemes, Miriam; Galic, Zoran; Phyu, Su; Okada, Hideho; Grausam, Katie B; Breunig, Joshua J; Brown, Christine E; Nathanson, David A; Prins, Robert M; Chen, Yvonne Y.
Afiliação
  • Hou AJ; Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA.
  • Shih RM; Department of Molecular Biology, University of California, Los Angeles, Los Angeles, CA.
  • Uy BR; Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA.
  • Shafer A; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA.
  • Chang ZNL; Department of Molecular Biology, University of California, Los Angeles, Los Angeles, CA.
  • Comin-Anduix B; Department of Surgery, University of California, Los Angeles, Los Angeles, CA.
  • Guemes M; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA.
  • Galic Z; Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, CA.
  • Phyu S; Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA.
  • Okada H; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA.
  • Grausam KB; Department of Neurosurgery, University of California, San Francisco, San Francisco, CA.
  • Breunig JJ; Department of Neurosurgery, University of California, San Francisco, San Francisco, CA.
  • Brown CE; Parker Institute for Cancer Immunotherapy Center at UCSF, San Francisco, CA.
  • Nathanson DA; Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
  • Prins RM; Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
  • Chen YY; Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, CA.
Neuro Oncol ; 2024 Jul 10.
Article em En | MEDLINE | ID: mdl-38982561
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-ß). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-ß-mediated immune suppression in the TME.

METHODS:

We engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-ß, which programs tumor-specific T cells to convert TGF-ß from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-ß 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-ß 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.

CONCLUSION:

Our findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-ß, bispecific IL-13Rα2/TGF-ß CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Idioma: En Revista: Neuro Oncol Assunto da revista: NEOPLASIAS / NEUROLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Idioma: En Revista: Neuro Oncol Assunto da revista: NEOPLASIAS / NEUROLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá