107 Armoring NKG2D CAR T cells with IL-18 improves in vivo anti-tumor activity

Background Whilst delivering impressive clinical efficacy in certain hematological malignancies, Chimeric Antigen Receptor (CAR) T cell therapy has yet to deliver significant impact across a broader array of cancer indications. Armoring CAR through the co-expression immune modifying cytokines is an approach that may aid anti-cancer activity but currently at embryonic stage development. In this study, potential benefit expressing IL-18 alongside NKG2D was assessed. Methods A series retroviral vectors encoding (a fusion with CD3z), surface tag facilitate selection and tracking (truncated CD19) either or without full length were compared. vectors, single shRNA targeting CD3z included generate allogeneic versions. All transgenes delivered as vector expressed under control promoter individual 2A elements ensuring equimolar levels protein expression. cells transduced challenged vitro vivo determine upon directed function. Results Armored transgene showed high secretion culture increased interferon gamma antigen challenge compared non-armored cells. also prolonged sequential target killing Importantly, stress test where dose reduced level minimal anti-tumor survival above seen using established THP-1 model, armored enhanced (as determined by bioluminescence) overall survival. Interestingly, doses cells, toxicity some tumor bearing models. This abrogated systemic infusion human binding (IL-18BP). Conclusions resulting target-dependent activity. The transient observed models eliminated IL-18BP. Together, these observations imply armoring likely drive improved line previous publications 1 2 while presence IL-18BP 3 should negate possible toxicities arising from constitutive expression cytokine. References Chmielewski M, Abken H. Cell Reports 2017; 21 (11): 3205–32192. Hu B, Ren J, Luo Y, Keith Young R, Scholler Zhao June C. 20(13): 3025–30333. Dinarello C, Novick D, Kim S, Kaplamski G. Frontiers Immunology 2013;4;289