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Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment.

Yeku OO1, Purdon TJ1, Koneru M1, Spriggs D1, Brentjens RJ2.

Author information

1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA.Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA. [e-mail].

Abstract

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.

https://www.ncbi.nlm.nih.gov/pubmed/28874817