Chimeric antigen receptor T cell (CAR T) therapy for solid tumors has not replicated the success seen with hematologic malignancies such as CD19-expressing B cell acute lymphoblastic leukemia (B-ALL) and Myeloma. One hypothesis for this lack of efficacy is an immunosuppressive tumor microenvironment that renders adoptively transferred cells ineffective. Armored CAR T cells are CAR T cells that have been further engineered to express additional costimulatory ligands, soluble cytokines or secretable proteins in order to overcome a hostile tumor microenvironment. IL-12 is a proinflammatory cytokine that is only secreted by antigen presenting cells and has been shown to activate effector cells, suppress regulatory T cells and reprogram tumor associated macrophages. We hypothesize that CAR T cells that have been genetically engineered to secrete IL-12 will be more efficacious in the treatment of Muc16ecto positive ovarian cancer by overcoming an otherwise immunosuppressive ascitic tumor microenvironment. Herein we report the mechanisms of enhanced efficacy of an IL-12-armored CAR T cell (4H1128ζ-IL12) directed towards the retained portion of Muc16 (Muc16ecto). Using an immunocompetent syngeneic peritoneal carcinomatosis model of ovarian cancer (i.p ID8-muc16ecto), we show superior therapeutic efficacy of armored CAR T cells compared to second generation CARs (4H1128ζ). Tumor-bearing mice treated after 35 days with 4H1128ζ-IL12 were tumor-free for over 100 days compared to 4H1128ζ-treated mice (o.s: not reached vs 46 days, p= 0.008). Even when the tumor was allowed to establish for 42 days, mice treated with 4H1128ζ-IL12 survived longer than 4H1128ζ- treated mice (o.s: 97 vs 54 days, p= 0.0123). Investigations into the mechanism of improved survival in armored CAR T cell-treated mice showed increased in vivo expansion and modulation of the immunosuppressive ascites cytokine milieu via increased secretion of IL-12, IFN-γ, and TNF-α. Furthermore, 4H1128ζ-IL12 CAR T cells demonstrated enhanced in vitro proliferation and cytotoxic activity when cultured in ascites compared to control CAR T cells. Taken together, these results show that armored CAR T cells can be successfully engineered to overcome an otherwise immunosuppressive solid tumor microenvironment. These results represent the mechanistic companion of an ongoing phase I clinical trial of IL-12 armored CAR T cells in patients with relapsed/refractory ovarian cancer (NCT02498912).
This abstract is also being presented as Poster A32.
Citation Format: Oladapo Yeku, Terence Purdon, David Spriggs, Renier Brentjens. Armored CAR T cells genetically modified to secrete IL-12 show enhanced efficacy and overcome a hostile tumor microenvironment in mouse ovarian peritoneal carcinomatosis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr PR08.