To improve anti-angiogenic therapies in VEGF-overexpressing solid tumors, Gao et al. engineered CAR T cells to secrete anti-VEGF scFvs (CAR-αVEGF T cells) and compared their efficacy with standard CAR T cell therapy alone or combined with anti-VEGF Ab. αVEGF-scFv secretion resulted in superior CAR T cell efficacy in ovarian cancer and orthotopic glioma models. Mechanistically, CAR-αVEGF T cells prevented treatment-induced angiogenesis and hypoxia, promoted CD8+ T cell activation and mitochondrial fitness, and boosted immune-stimulatory myeloid phenotypes, while decreasing infiltration of suppressive, VEGF-expressing myeloid cells.
Contributed by Katherine Turner
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-_VEGF 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-_VEGF 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-_VEGF T cells as a safe and potent therapy for solid tumors characterized by elevated VEGF.
Author Info: (1) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Ge
Author Info: (1) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (2) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. (3) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (4) Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115201, Taiwan. (5) Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. (6) Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. (7) Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. (8) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (9) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (10) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (11) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. (12) Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. (13) Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. (14) Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA. VA Greater Los Angeles Healthcare System, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. (15) Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115201, Taiwan. (16) Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, CA 90095, USA.
