Abstract
A hypoxic microenvironment is a hallmark of cancer that has been shown in numerous cancer types to drive tumor progression and poor patient outcomes. Hypoxia promotes tumor evasion of the host immune responses by generating an immunosuppressive tumor microenvironment through activation of multiple pathways mediated predominantly, but not exclusively, by hypoxia inducible factor-1 (HIF-1) signaling. We have previously shown that Omniox' lead anti-cancer immunotherapeutic, OMX, is well tolerated in small and large animals, efficiently accumulates in a variety of orthotopic and subcutaneous rodent tumor models and spontaneous canine melanomas and brain cancers, and effectively reduces tumor hypoxia as assessed by ex vivo immunoassays using hypoxia markers, in vivo FMISO PET imaging, and direct intratumor pO2 measurements with optical probes. Here, we used a combination of quantitative immunohistochemistry and flow cytometry to analyze the effects of OMX treatment and dosing regiment on leukocyte infiltration and activity in normoxic and hypoxic tumor regions in multiple syngeneic mouse tumor models (MC38, CT26, 4T1, B16F10). First, we confirmed in our models published findings that cytotoxic T cells (CTL) are predominantly excluded from hypoxic tumor areas. Next, we explored the effect of single and multi-dose OMX treatments on tumor immune cell populations, and demonstrated that a single iv administration of OMX reduces hypoxia and enhances T cell localization in previously hypoxic tumor areas labelled by two independent markers of hypoxia (pimonidazole and CAIX). Furthermore, 12h after a single OMX treatment we observed >85% intra-tumor reduction in immunosuppressive regulatory T cells (Treg). Tumor Treg reduction was maintained and even more pronounced with repeated dosing, resulting in long-term Treg depletion. Importantly, OMX treatment resulted in a 5-10 fold higher CTL/Treg ratio concomitant with a 3-fold increase in the fraction of activated effector T lymphocytes, with no effect on overall leukocyte populations within the tumor. Taken together, our data suggest that OMX treatment changes the tumor microenvironment from an immunosuppressive to an immunopermissive state in multiple tumor types. Results from ongoing OMX+checkpoint inhibitor combination studies will also be presented. In conclusion, by delivering oxygen specifically to the hypoxic tumor microenvironment, OMX may restore anti-cancer immune responses in cancer patients. Given that OMX is well-tolerated and that its mechanism of action is upstream of major immunosuppressive pathways, OMX holds the potential to synergize with multiple immunotherapeutic agents in enhancing tumor control and improving patient outcomes in solid tumors.
Citation Format: Kevin G. Leong, Natacha Le Moan, Yuqiong Pan, Philberta Leung, Catherine Bedard, Jon Winger, Stephen PL Cary, Ana Krtolica. OMX: An oxygen carrier biotherapeutic that ameliorates the hypoxic tumor microenvironment and promotes anticancer T cell activity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B029.
