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Engineered CXCR3-A expression enhances B7-H3-targeting CAR T cell migration and efficacy against diffuse intrinsic pontine glioma

Author

Listed:
  • Edward Z. Song

    (Seattle Children’s Research Institute)

  • Andrea Timpanaro

    (Seattle Children’s Research Institute)

  • Michael Meechan

    (Seattle Children’s Research Institute)

  • Leonel Elena-Sanchez

    (Seattle Children’s Research Institute)

  • Lucy Z. Li

    (Benaroya Research Institute
    University of Washington
    University of Washington)

  • Sophie Jamet

    (Seattle Children’s Research Institute)

  • Davina S. Lau

    (Seattle Children’s Research Institute)

  • Lily I. Winter

    (Seattle Children’s Research Institute)

  • Matthew D. Dun

    (University of Newcastle
    University of Newcastle
    New Lambton Heights)

  • Jessica B. Foster

    (University of Pennsylvania Perelman School of Medicine
    Children’s Hospital of Philadelphia)

  • Myron K. Evans

    (Seattle Children’s Research Institute)

  • Siobhan S. Pattwell

    (Seattle Children’s Research Institute)

  • Vandana Kalia

    (Seattle Children’s Research Institute)

  • Surojit Sarkar

    (Seattle Children’s Research Institute
    University of Washington)

  • Michael C. Jensen

    (Seattle Children’s Therapeutics)

  • Matthew C. Biery

    (Seattle Children’s Research Institute)

  • Nicholas A. Vitanza

    (Seattle Children’s Research Institute
    University of Washington)

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a fatal brainstem tumor desperately in need of better treatments. Chimeric antigen receptor (CAR) T cell therapies for DIPG have demonstrated clinical tolerability and bioactivity, but not universal benefit. A major obstacle is insufficient CAR T cell trafficking to the tumor. As our recent clinical trials have demonstrated locoregional elevation of CXCL10, a ligand of the chemokine receptor CXCR3, here we aim to leverage this CXCL10 upregulation to enhance cell trafficking by engineering our B7-H3-targeting CAR T cells to overexpress CXCR3 variants. We demonstrate that, compared to unmodified B7-H3 CAR T cells, CXCR3-A-modified CAR T cells migrate more efficiently toward CXCR3 ligands in vitro, and when delivered intracerebroventricularly in orthotopic DIPG mouse models, CXCR3-A-modified CAR T cells show enhanced trafficking into the tumor and improved therapeutic efficacy. Overall, our data support the potential for engineering CXCR3-A expression to enhance CAR T cell trafficking and efficacy against DIPG.

Suggested Citation

  • Edward Z. Song & Andrea Timpanaro & Michael Meechan & Leonel Elena-Sanchez & Lucy Z. Li & Sophie Jamet & Davina S. Lau & Lily I. Winter & Matthew D. Dun & Jessica B. Foster & Myron K. Evans & Siobhan , 2025. "Engineered CXCR3-A expression enhances B7-H3-targeting CAR T cell migration and efficacy against diffuse intrinsic pontine glioma," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64861-6
    DOI: 10.1038/s41467-025-64861-6
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    References listed on IDEAS

    as
    1. Hongxia Li & Emily B. Harrison & Huizhong Li & Koichi Hirabayashi & Jing Chen & Qi-Xiang Li & Jared Gunn & Jared Weiss & Barbara Savoldo & Joel S. Parker & Chad V. Pecot & Gianpietro Dotti & Hongwei D, 2022. "Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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