Secretion of a VEGF-Blocking scFv Enhances CAR T-cell Potency.
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Abstract | Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment strategy for B-cell malignancies; however, its efficacy in solid tumors remains limited. VEGF-targeted drugs are used as antitumor agents to target abnormal tumor vasculature; however, toxicities associated with systemic VEGF blockade limit their maximal therapeutic benefit. Increasing evidence suggests a role for VEGF in the immunosuppressive tumor microenvironment, including through direct induction of T cell-effector dysfunction. In this study, we show that CAR T cells from patients treated with FDA-approved CAR T-cell products express members of the VEGF signaling pathway, and this expression is correlated with patient nonresponse. To overcome putative VEGF-induced CAR T-cell dysfunction and deliver local VEGF blockade, we generated CAR T cells that secrete a VEGF-targeting single-chain variable fragment to block T-cell and tumor-derived VEGF within the tumor microenvironment. These CAR T cells potently inhibited VEGF signaling and angiogenesis in vitro and exhibited enhanced activation, cytotoxicity, proliferation, and effector function across different antigen and solid tumor contexts. VEGF single-chain variable fragment-secreting CAR T cells showed improved tumor control in immunocompromised murine metastatic and orthotopic models of ovarian and lung cancer. These findings suggest that CAR T cell-secreted VEGF blockade augments CAR T-cell performance, inhibits VEGF without systemic toxicity, and warrants further development. |
Year of Publication | 2025
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Journal | Cancer immunology research
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Volume | 13
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Issue | 8
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Pages | 1132-1144
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Date Published | 08/2025
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ISSN | 2326-6074
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DOI | 10.1158/2326-6066.CIR-24-0876
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PubMed ID | 40455064
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