Secretion of a VEGF-Blocking scFv Enhances CAR T-cell Potency

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.

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Publication Details

Journal
Cancer Immunology Research
Published
2025-06-02
DOI
https://doi.org/10.1158/2326-6066.cir-24-0876
Citations
7
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
7.32

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article

Secretion of a VEGF-Blocking scFv Enhances CAR T-cell Potency

Felix Korell, Mark B. Leick, Marcela V. Maus, Diego Salas‐Benito et al.
7 citations
Cancer Immunology Research
CAR-T cell therapy research
7.32
article

Secretion of a VEGF-Blocking scFv Enhances CAR T-cell Potency

Felix Korell, Mark B. Leick, Marcela V. Maus, Diego Salas‐Benito, Eli P. Darnell, Bryan D. Choi, Michael C. Kann, Valentina M. Supper, Tamina Kienka, H. TAKEI, Filippo Birocchi, Nicholas J. Haradhvala, Hannah Donner, Aiyana Parker, Amanda A. Bouffard, Grace Martin, Giulia Escobar, Stefanie R. Bailey, Sangwoo Park, Alexander Armstrong, Merle Philips, Sadie Goncalves, Alexandra Bratt
article en
7 citations

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.

Cancer Immunology ResearchVol. 13(8)
Broad Institute (US), Harvard University (US), Massachusetts General Hospital (US), Center for Cancer Research (US), University of Virginia (US), Massachusetts Institute of Technology (US)
American Cancer Society, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 3%
CAR-T cell therapy research
7.32
DOIOpen Access PDFOpenAlex
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