Abstract 1744: Reversal of advanced colitis-associated colon cancer by OMX, a novel oxygen carrier that immunosensitizes the hypoxic tumor microenvironment

Abstract

Abstract Chronic inflammation of the colon increases cancer development risk. Ulcerative colitis, characterized by excessive inflammation initiated by innate immune cells and exacerbated by a dysregulation in adaptive immunity, can give rise to colitis-associated colon cancer (CAC). Whereas overactivity of effector T cells and loss of immunosuppressive cells are hallmarks of ulcerative colitis, the opposite is true for CAC, with CAC tumors exhibiting a lack of effector T cell infiltration and a preponderence of immunosuppressive Treg cells and myeloid-derived suppressor cells (MDSCs). Recently, hypoxia has been identified as a potential driver in the pathogenesis of ulcerative colitis, with hypoxia persisting upon progression to CAC tumor formation. We have previously demonstrated that (i) hypoxia generates an immunosuppressive tumor microenvironment that limits effector T cell infiltration and activation, (ii) OMX, a first-in-class anti-cancer therapy designed to reverse tumor hypoxia to enhance immunotherapeutic efficacy, accumulates in preclinical rodent and spontaneous canine tumors and reduces tumor hypoxia, and (iii) OMX promotes effector T cell infiltration, reduces Treg cells, and enhances checkpoint inhibitor efficacy, resulting in greater tumor control. Given that CAC tumors are hypoxic and immunosuppressed, we hypothesized that hypoxia drives CAC tumor immunosuppression, and accordingly, that reversal of hypoxia with OMX may restore immunosensitivity and elicit an anti-tumor response. Here, using a chemically induced mouse model of CAC generated by administering azoxymethane (AOM) followed by repeated cycles of dextran sulfate sodium (DSS) exposure, we show that OMX treatment exhibits anti-tumor efficacy in advanced CAC tumors. We characterized CAC tumor progression from 8 to 12 weeks post-tumor induction, and confirmed previous reports that advanced CAC tumors are indeed hypoxic, and that immunosuppressive Treg cells and MDSCs are more abundant in CAC tumors relative to adjacent normal mucosa or control non-AOM/DSS-treated colons. Moreover, we observed a negative correlation between hypoxia and CD8+ T cell infiltration into CAC tumors. OMX single agent treatment reduced both CAC tumor number and total CAC tumor burden. Of note, OMX treatment reversed colon length shortening that was characteristic of tumor-bearing mice, indicative of a restoration of colon crypt regeneration and hence normal colon biology. Investigations into the immunological mechanism(s) responsible for OMX anti-tumor efficacy are currently underway. Taken together, our data suggest that OMX, by delivering oxygen to hypoxic CAC tumor regions, may be sufficient to induce an immunological change in the CAC tumor microenvironment from an immunosuppressive to an immunopermissive state, leading to tumor responses and a restoration of normal physiology. Citation Format: Kevin G. Leong, Yuqiong Pan, Changan Guo, Padmini Narayanan, Jonathan A. Winger, Stephen P. Cary, Natacha Le Moan, Ana Krtolica. Reversal of advanced colitis-associated colon cancer by OMX, a novel oxygen carrier that immunosensitizes the hypoxic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1744.