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Background: STING is an endogenous sensor of cGAMP, which is synthesized by cGAS following detection of cytoplasmic DNA. STING activation leads to interferon production and activation of inflammatory pathways that facilitate cytolytic T cell priming. STING agonists administered intratumorally show potent anti-tumor efficacy in a range of preclinical models; several agonists are in clinical development. Radiation therapy also increases cytoplasmic DNA levels in cancer cells, resulting in STING activation and secretion of inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates STING by hydrolyzing cGAMP. MV-626, a highly potent and selective ENPP1 inhibitor with 100% oral bioavailability in rats and mice, blocks cGAMP hydrolysis and increases STING activation in cells where cGAS is active. We hypothesize that by conditionally enhancing STING activation, ENPP1 inhibitors will facilitate development of anti-tumor cellular immune responses, particularly following radiation therapy.
Methods: The effects of ENPP1 inhibition on STING activation using cGAMP or DNA treatment of cells were assessed. Panc02-SIY tumors were implanted in C57BL/6 mice and randomized to receive 20Gy CT-guided radiation therapy, 5 daily ip doses of MV-626, or both MV-626 and radiation. Mice were followed for outcome, tumor antigen specific T cell responses and changes in the tumor immune environment. Additional studies were conducted in mice bearing MC38 tumors.
Results: In vitro, MV-626 blocks ENPP1-mediated hydrolysis of cGAMP and enhances STING activation by DNA-mediated cGAS activation or exogenous cGAMP. Therapeutic doses of MV-626 were well tolerated in mice, with no evidence of toxicity or clinically-significant increases in systemic cytokine levels. Systemic administration of MV- 626 monotherapy caused tumor growth delay. MV-626 combined with radiation therapy significantly increased overall survival, and most animals achieved durable tumor cures. Additional studies in the MC38 model confirmed MV-626 activity. Studies characterizing effects of MV-626 in the tumor microenvironment are underway.
Conclusions: These data demonstrate that a potent, selective ENPP1 inhibitor augments STING activation and enhances immune responses to tumors. We demonstrate for the first time that, in combination with radiation therapy, ENPP1 inhibition improves outcomes and cures tumors in preclinical models through changes in the tumor immune environment. These translational studies represent a novel approach to enhancing tumor directed immune response following radiation, and provide a foundation for clinical development of an ENPP1 inhibitor as a cancer immunotherapy.
Cancer, immunotherapy, cytokines, tumor microenvironment, T cells, radiation therapy, cancer immunity, STING
Baird, Jason; Dietsch, Gregory; Florio, Vincent; Gallatin, Michael; Knox, Clayton; Odingo, Joshua; Crittenden, Marka; and Gough, Michael J., "MV-626, a potent and selective inhibitor of ENPP1 enhances STING activation and augments T-cell mediated anti-tumor activity in vivo" (2018). Society for Immunotherapy of Cancer 2018 Annual Meeting Posters. 7.