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Secretion of a VEGF-Blocking scFv Enhances CAR T-cell Potency
Valentina M Supper1, Hannah Donner1, Filippo Birocchi1
1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts.
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.
Insights
Engineered CAR T-cells secreting a VEGF-targeting antibody fragment overcome tumor defenses. This approach enhances CAR T-cell therapy efficacy against solid tumors by blocking immunosuppressive VEGF signaling locally, improving anti-tumor responses.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise for B-cell malignancies but has limited efficacy in solid tumors.
- Vascular Endothelial Growth Factor (VEGF) blockade is an antitumor strategy, but systemic toxicities limit its use.
- VEGF contributes to an immunosuppressive tumor microenvironment, impairing T-cell function.
Purpose of the Study:
- To investigate VEGF signaling pathway expression in CAR T cells from patients.
- To develop CAR T cells engineered to locally block VEGF within the tumor microenvironment.
- To evaluate the efficacy of VEGF-blocking CAR T cells in solid tumor models.
Main Methods:
- CAR T cells from patients were analyzed for VEGF signaling pathway members.
- CAR T cells were engineered to secrete a VEGF-targeting single-chain variable fragment (scFv).
- In vitro and in vivo studies were conducted using solid tumor models (ovarian and lung cancer).
Main Results:
- CAR T cells from non-responding patients expressed VEGF signaling pathway members.
- Engineered CAR T cells potently inhibited VEGF signaling and angiogenesis in vitro.
- VEGF-blocking CAR T cells demonstrated enhanced activation, cytotoxicity, proliferation, and effector function.
- Improved tumor control was observed in murine models of ovarian and lung cancer.
Conclusions:
- CAR T cell-secreted VEGF blockade enhances CAR T-cell performance in solid tumors.
- This strategy inhibits VEGF locally without systemic toxicity.
- Engineered CAR T cells warrant further development for solid tumor treatment.
