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Engineering CAR T cells to secrete VEGF-neutralizing scFvs enhances antitumor activity against solid tumors
Torahito A Gao1,2, Ryan M Shih2,3, Justin D Clubb1,2
1Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Science Translational Medicine
|March 4, 2026
Summary
Engineered CAR T cells secreting anti-VEGF (CAR-αVEGF T cells) show enhanced efficacy against solid tumors. This novel therapy improves T cell function and overcomes tumor microenvironment-mediated immunosuppression.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Solid tumors often exhibit immunosuppressive tumor microenvironments (TMEs).
- Vascular endothelial growth factor A (VEGF) in TMEs promotes immunosuppression and abnormal tumor vasculature.
- Conventional chimeric antigen receptor (CAR) T cell therapy has limited success against solid tumors.
Purpose of the Study:
- To evaluate the efficacy of CAR T cells engineered to secrete anti-VEGF (CAR-αVEGF T cells) against solid tumors.
- To investigate the mechanisms by which CAR-αVEGF T cells overcome TME-induced immunosuppression.
- To assess the safety and potency of CAR-αVEGF T cells compared to conventional CAR T cells and combination therapies.
Main Methods:
- In vivo studies using ovarian cancer and glioma models.
- Microscopy, flow cytometry, and transcriptomic analyses.
- Engineering CAR T cells to secrete anti-VEGF single-chain variable fragments.
Main Results:
- CAR-αVEGF T cells demonstrated superior antitumor efficacy compared to conventional CAR T cells.
- Engineered CAR T cells showed enhanced activation, mitochondrial fitness, and immune-stimulatory signatures.
- CAR-αVEGF T cells mitigated detrimental effects like myeloid cell infiltration, vascular abnormalities, and hypoxia.
Conclusions:
- CAR-αVEGF T cells represent a promising therapeutic strategy for solid tumors with elevated VEGF.
- This approach enhances CAR T cell function and overcomes immunosuppressive tumor microenvironments.
- Clinical translation of CAR-αVEGF T cells is warranted for solid tumor treatment.
