Yeku et al. delineated the mode of action of Muc-16-directed “armored” CAR T cells that constitutively secrete IL-12. In an aggressive murine disseminated ovarian cancer model, these cells maintained efficacy, demonstrated enhanced antitumor function, and improved overall survival. The armored CAR T cells evaded immune suppression by phenotypic skewing and Fas/FasL-dependent depletion of tumor-associated macrophages, and by resisting inhibition by PD-L1.
Chimeric antigen receptor (CAR) T cell therapy has shown limited efficacy for the management of solid tumor malignancies. In ovarian cancer, this is in part due to an immunosuppressive cytokine and cellular tumor microenvironment which suppresses adoptively transferred T cells. We engineered an armored CAR T cell capable of constitutive secretion of IL-12, and delineate the mechanisms via which these CAR T cells overcome a hostile tumor microenvironment. In this report, we demonstrate enhanced proliferation, decreased apoptosis and increased cytotoxicity in the presence of immunosuppressive ascites. In vivo, we show enhanced expansion and CAR T cell antitumor efficacy, culminating in improvement in survival in a syngeneic model of ovarian peritoneal carcinomatosis. Armored CAR T cells mediated depletion of tumor associated macrophages and resisted endogenous PD-L1-induced inhibition. These findings highlight the role of the inhibitory microenvironment and how CAR T cells can be further engineered to maintain efficacy.