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Activated STING (STimulator of INterferon Genes) bound to its natural ligand 2,3-cGAMP (cyclic guanosine-adenosine monophosphate), initiates type I interferon (IFN) and pro-inflammatory cytokine production. IFN upregulation is essential to promote antigen-specific CD8+ T-cell priming and leads to potent anti-tumor activity. To exploit this mechanism we synthesized a new STING agonist, MSA-1, that potently activates both mouse and human STING. Intratumoral (IT) administration of MSA-1 to MC38 syngeneic tumor-bearing mice increased tumor and plasma cytokine levels and was effective at driving complete responses (CRs) in 100% of the animals. Most surviving animals developed tumor-specific adaptive immune memory as demonstrated by robust protection against re-challenge with the same tumor type. Mechanistic studies in immune-deficient mice suggested that the initial antitumor activity is in part due to cytokine-driven cytotoxicity and/or other innate immune mechanisms, which may have contributed to some animals not developing an adaptive immune memory. Importantly, MSA-1 caused long-term tumor regressions or CRs in CT26 and B16-F10 tumor models, both of which are intrinsically resistant to single-agent therapy with a fully murinized anti-mouse PD-1 antibody (muDX400). The antitumor immune response in these models was further enhanced when treating the animals with MSA-1 in combination with muDX400. This combination restored T-cell responses in both blood and tumors of the treated mice and provided long-lived immunologic memory in a majority of the animals. Taken together, these data strongly support the development of STING agonists in combination with Keytruda (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single agent anti-PD-1 therapy. Citation Format: Samanthi A. Perera, Johnny E. Kopinja, Yanhong Ma, Jason Laskey, Kalyan Chakravarthy, Long Cui, Yiping Chen, Jeremy Presland, Sharad Sharma, Shuxia Zhao, Jennifer Piesvaux, Ellen C. Minnihan, Heidi Ferguson, Hyun Chong Woo, Ian Knemeyer, Ilona Kariv, Archie Tse, Saso Cemerski, Jared Cumming, B. Wesley Trotter, Bo-Sheng Pan, George H. Addona, Brian J. Long. Combination with a novel STING agonist significantly improves efficacy of anti-PD1 therapy in mouse syngeneic tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A08.