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

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 and Nicholas A. Vitanza ()
Additional contact information
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
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
Jessica B. Foster: University of Pennsylvania Perelman School of Medicine
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
Michael C. Jensen: Seattle Children’s Therapeutics
Matthew C. Biery: Seattle Children’s Research Institute
Nicholas A. Vitanza: Seattle Children’s Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64861-6

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