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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月11日

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  • 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 S. Pattwell,
  • Vandana Kalia,
  • Surojit Sarkar,
  • Michael C. Jensen,
  • Matthew C. Biery,
  • Nicholas A. Vitanza

摘要

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.