Engineering CAR T cells to secrete VEGF-neutralizing scFvs enhances antitumor activity against solid tumors

Sci Transl Med. 2026 Mar 4;18(839):eadw9286. doi: 10.1126/scitranslmed.adw9286. Epub 2026 Mar 4.

Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy against solid tumors, which often reside in highly immunosuppressive tumor microenvironments (TMEs). TMEs can be highly abundant in vascular endothelial growth factor A (VEGF), which contributes to immunosuppression and abnormal tumor vasculature. Here, we found that CAR T cells engineered to secrete an anti-VEGF single-chain variable fragment (CAR-αVEGF T cells) achieved superior antitumor efficacy against multiple in vivo models of ovarian cancer and glioma, outperforming conventional CAR T cells with and without combination anti-VEGF antibody therapy. Microscopy, flow cytometry, and transcriptomic analyses revealed that armoring the CAR T cells with anti-VEGF single-chain variable fragments enhanced their activation and mitochondrial fitness and enriched immune-stimulatory signatures among endogenous immune cells in the tumor-bearing brain. Moreover, CAR-αVEGF T cells circumvented multiple detrimental effects associated with on-target CAR T cell therapy, including infiltration of suppressive myeloid cells, exaggerated vasculature abnormalities, and hypoxia. Together, our results provide rationale for the clinical translation of CAR-αVEGF T cells as a safe and potent therapy for solid tumors characterized by elevated VEGF.

MeSH terms

  • Animals
  • Antibodies, Neutralizing* / immunology
  • Cell Line, Tumor
  • Female
  • Glioma / immunology
  • Glioma / pathology
  • Glioma / therapy
  • Humans
  • Immunotherapy, Adoptive
  • Mice
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / therapy
  • Receptors, Chimeric Antigen* / metabolism
  • Single-Chain Antibodies* / metabolism
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / metabolism
  • Tumor Microenvironment
  • Vascular Endothelial Growth Factor A* / immunology
  • Vascular Endothelial Growth Factor A* / metabolism

Substances

  • Vascular Endothelial Growth Factor A
  • Receptors, Chimeric Antigen
  • Single-Chain Antibodies
  • Antibodies, Neutralizing