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Engineered CXCR3-A expression enhances B7-H3-targeting CAR T cell migration and efficacy against diffuse intrinsic
Edward Z Song1, Andrea Timpanaro1, Michael Meechan1
1Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA, USA.
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.
Insights
Engineered CAR T cells overexpressing CXCR3-A show improved trafficking to Diffuse Intrinsic Pontine Glioma (DIPG) tumors. This enhancement in cell delivery boosts therapeutic efficacy against this fatal brainstem cancer.
Area of Science:
- Oncology
- Immunotherapy
- Neuroscience
Background:
- Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brainstem tumor with limited treatment options.
- Chimeric antigen receptor (CAR) T cell therapy shows promise but faces challenges with tumor cell trafficking.
- CXCL10, a ligand for CXCR3, is upregulated in DIPG tumors, presenting a potential target for enhancing cell delivery.
Purpose of the Study:
- To engineer B7-H3-targeting CAR T cells to overexpress CXCR3 variants to improve trafficking to DIPG tumors.
- To evaluate the in vitro migration and in vivo therapeutic efficacy of CXCR3-modified CAR T cells in DIPG models.
Main Methods:
- Genetic engineering of B7-H3 CAR T cells to overexpress CXCR3 variants (specifically CXCR3-A).
- In vitro migration assays assessing T cell response to CXCR3 ligands.
- Intracerebroventricular administration of engineered CAR T cells in orthotopic DIPG mouse models.
Main Results:
- CXCR3-A-modified CAR T cells exhibited enhanced migration towards CXCR3 ligands in vitro compared to unmodified CAR T cells.
- Intracerebroventricular delivery of CXCR3-A CAR T cells resulted in improved trafficking into DIPG tumors in mouse models.
- Therapeutic efficacy was significantly improved in mice treated with CXCR3-A-modified CAR T cells.
Conclusions:
- Engineering CAR T cells with CXCR3-A enhances their trafficking to DIPG tumors.
- This strategy holds potential for improving CAR T cell therapy efficacy against DIPG.
- Targeting the CXCL10/CXCR3 axis represents a promising approach for DIPG treatment.
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