And secretion of inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) will be the phosphodiesterase that negatively regulates STING by hydrolyzing cGAMP. MV-626, a highly potent and selective ENPP1 inhibitor with one hundred 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 improvement of anti-tumor cellular immune responses, specifically following radiation therapy. Techniques The effects of ENPP1 inhibition on STING activation applying cGAMP or DNA treatment of cells have been assessed. Panc02-SIY tumors were implanted in C57BL/6 mice and randomized to get 20Gy CT-guided radiation therapy, 5 every day ip doses of MV-626, or both MV-626 and radiation. Mice had been followed for outcome, tumor antigen certain T cell responses and alterations in the tumor immune atmosphere. Added research have been 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 have been effectively tolerated inJournal for ImmunoTherapy of Cancer 2018, six(Suppl 1):Page 214 ofmice, with no evidence of toxicity or clinically-significant increases in Ubiquitin-Specific Peptidase 29 Proteins Storage & Stability systemic cytokine levels. Systemic administration of MV- 626 monotherapy triggered tumor development delay. MV-626 combined with radiation therapy considerably improved all round survival, and most animals accomplished sturdy tumor cures. Further research within the MC38 model confirmed MV-626 activity. Research characterizing effects of MV-626 within 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 by way of changes in the tumor immune environment. These translational research represent a novel method to enhancing tumor directed immune response following radiation, and supply a foundation for clinical improvement of an ENPP1 inhibitor as a cancer immunotherapy. P411 An IL15/IL15R heterodimeric Fc-fusion engineered for reduced potency demonstrates an Ubiquitin Conjugating Enzyme E2 B Proteins Purity & Documentation optimal balance of in vivo activity and exposure Matthew Bernett, PhD1, Rajat Varma, PhD1, Christine Bonzon, PhD1, Liz Bogaert, PhD1, Rumana Rashid, PhD1, Ke Liu, PhD1, Irene Leung, PhD1, Suzanne Schubbert, PhD1, Sung-Hyung Lee, PhD1, Daniel Kirouac, PhD2, Fei Hua, PhD2, Nicole Rodriguez, PhD1, Yoon Kim, PhD1, Kendra Avery, PhD1, Connie Ardila1, Nargess Hassanzadeh- Kiabi, PhD1, Umesh Muchhal, PhD1, Seung Chu, PhD1, Gregory Moore, PhD1, John R. Desjarlais1 1 Xencor Inc., Monrovia, CA, USA; 2Applied BioMath, LLC, Oakland, CA, USA Correspondence: John R. Desjarlais ([email protected]) Journal for ImmunoTherapy of Cancer 2018, 6(Suppl 1):P411 Background IL15 and IL2 are related cytokines that bind towards the IL2R/c receptor complex and induce the proliferation of lymphocytes. Their therapeutic prospective has been nicely established in animal models and human trials. As possible drugs, each IL2 and IL15 are particularly potent and suffer from low tolerability and quite fast clearance that limits therapeutic window. To engineer a more druggable version of IL15, we designed several IL15/IL15R heterodimeric Fc-fusi.
