Engineered CXCR3-A expression enhances the trafficking and efficacy of intracerebroventricularly delivered B7-H3-targeting CAR T cells against diffuse intrinsic pontine glioma

Diffuse intrinsic pontine glioma (DIPG) is a fatal brainstem tumor desperately in need of better treatments. 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 clinical trials have demonstrated locoregional elevation of CXCL10, a ligand of the chemokine receptor CXCR3, we aimed to leverage this CXCL10 to enhance cell trafficking by engineering our B7-H3-targeting CAR T cells to overexpress CXCR3 variants. Here, 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.