Engineered CXCR3-A expression enhances B7-H3-targeting CAR T cell migration and efficacy against diffuse intrinsic pontine glioma
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.
Authors
- Sophie Jamet (ORCID: https://orcid.org/0000-0002-4490-7080)
- Michael C. Jensen (ORCID: https://orcid.org/0000-0001-7477-3063)
- Matthew C. Biery (ORCID: https://orcid.org/0000-0001-6152-3604)
- Myron K. Evans (ORCID: https://orcid.org/0000-0002-7678-5815)
- Matthew D. Dun (ORCID: https://orcid.org/0000-0002-9063-5370)
- Jessica Foster (ORCID: https://orcid.org/0000-0002-8001-5960)
- Nicholas A. Vitanza (ORCID: https://orcid.org/0000-0002-3966-4985)
- Siobhan S. Pattwell (ORCID: https://orcid.org/0000-0003-4434-3139)
- Andrea Timpanaro (ORCID: https://orcid.org/0000-0003-3955-3481)
- Lucy Z. Li (ORCID: https://orcid.org/0000-0003-4616-736X)
- Lily I. Winter (ORCID: https://orcid.org/0009-0002-3868-3284)
- Edward Z. Song (ORCID: https://orcid.org/0000-0002-4022-9753)
- Michael Meechan (ORCID: https://orcid.org/0000-0003-2710-606X)
- Leonel Elena-Sanchez
- Davina Lau (ORCID: https://orcid.org/0009-0005-3744-868X)
- Vandana Kalia (ORCID: https://orcid.org/0000-0001-6250-2151)
- Surojit Sarkar (ORCID: https://orcid.org/0000-0003-1940-1878)
Institutions
- Seattle Children's Hospital (US)
- Children's Hospital of Philadelphia (US)
- University of Washington (US)
- Hunter Medical Research Institute (AU)
- Seattle Children's Hospital (US)
- Center for Cancer and Blood Disorders (US)
- Benaroya Research Institute
- University of Newcastle Australia (AU)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1038/s41467-025-64861-6
- Citations
- 4
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- Washington Research Foundation
- Fred Hutchinson Cancer Research Center
- University of Washington
- National Institutes of Health
- National Cancer Institute