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Targeting VEGF to enhance CAR T-cell function in solid tumors

Gao TA, Shih RM, Clubb JD, et al. Engineering CAR T Cells to Secrete VEGF-Neutralizing scFvs Enhances Antitumor Activity Against Solid Tumors. Translational Behavior Medicine. 2026; (doi: 10.1126/scitranslmed.adw9286).

Investigators designed chimeric antigen receptor (CAR) T cells to work against vascular endothelial growth factor A (VEGF), a protein that contributes to immunosuppressive tumor microenvironments (TMEs), with encouraging results. The cells were armored with anti-VEGF single-chain variable fragments (scFvs) to enhance activation and mitochondrial fitness. They were also engineered to release anti-VEGF scFvs. The two-pronged strategy, tested in multiple in vivo models of ovarian cancer and glioma, yielded superior antitumor efficacy compared with conventional CAR T cells and appeared to mitigate damage related to the immunotherapy itself. Specifically, damage stemming from suppressive myeloid cells, exaggerated vasculature abnormalities, and hypoxia was reduced. While the immunosuppressive TME observed in many solid tumors has historically limited the efficacy of CAR T interventions in this setting, the study authors believe they have identified a safe and powerful treatment approach, at least in the context of malignancies presenting with high VEGF levels.

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