Analyzing scRNAseq data from CAR T cell infusion products, Supper and Donner et al. found that VEGFR1 was expressed in 41BB.z CAR T cells and associated negatively with treatment response. In vitro, activation increased VEGFR1 expression on 41BB.z, but not 28.z CAR T cells; activated CAR T cells also secreted VEGF. To block VEGF signaling, CAR T cells were engineered to secrete an anti-VEGF scFv. This modification (cf. a nonspecific scFv) improved CAR T cell expansion in target cell coculture, and tumor infiltration and antitumor efficacy in vivo. VEGF and endothelial cells were diminished around the engineered CAR T cells in tumors.
Contributed by Alex Najibi
ABSTRACT: CAR T-cell therapy is an effective treatment strategy in 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 (TME), including through direct induction of T cell-effector dysfunction. Herein, 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 non-response. To overcome putative VEGF-induced CAR T-cell dysfunction and deliver local VEGF blockade, we generated CAR T cells that secrete a VEGF-targeting scFv to block T-cell and tumor-derived VEGF within the TME. 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 scFv-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.
Author Info: (1) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (2) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (3)
Author Info: (1) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (2) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (3) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (4) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (5) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (6) Massachusetts General Hospital, Charlestown, MA, United States. (7) Massachusetts General Hospital, United States. (8) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (9) Massachusetts General Hospital, Charlestown, MA, United States. (10) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (11) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (12) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (13) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (14) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (15) University of Virginia, Charlestown, MA, United States. (16) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (17) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (18) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (19) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (20) Massachusetts General Hospital, Boston, United States. (21) Massachusetts General Hospital, Boston, MA, United States. (22) Massachusetts General Hospital, Charlestown, MA, United States. (23) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States.
