The oxygen carrier OMX restores anti-tumor immunity and when combined with checkpoint inhibitors improves anti-tumor efficacy in orthotopic and subcutaneous tumor models
Natacha Le Moan1, Kevin G Leong1, Philberta Leung1, Yuqiong Pan1, Sarah Ng1, Tina Davis1, Carol Liang1, Jonathan Winger1, Stephen P.L. Cary1, Nicholas Butowski2, and Ana Krtolica1
1Omniox Inc., 75 Shoreway, Suite B, San Carlos, CA 94070, USA
2University of California at San Francisco, San Francisco, California
Intratumoral hypoxia is associated with resistance to chemo- and radio-therapies and poor patient outcomes. Hypoxia promotes immune tolerance by altering the recruitment and function of innate and adaptive immune effector and suppressor cells. Therefore, creating an immunopermissive microenvironment by reversing tumor hypoxia provides an attractive combinatorial approach to improve immunotherapy response in solid tumors.
OMX is an oxygen carrier well-tolerated in rodents and large animals (sheep and dog). Following intravenous dosing, OMX extravasates through leaky tumor vasculature, accumulates in tumor tissues, and specifically delivers oxygen to hypoxic tumor regions. Consequently, OMX significantly reduces hypoxia in multiple orthotopic and immunocompetent rodent tumor models and spontaneous canine brain tumor patients.
Here we used a combination of immunohistochemical, flow cytometric, and multiplex cytokine analyses to evaluate OMX’ ability to reverse the immunosuppressive phenotype of the tumor microenvironment in the GL261 intracranial glioblastoma model.
Similar to previously published findings, we demonstrated that T lymphocytes are mostly excluded from hypoxic tumor areas in GL261 tumors. A single dose of OMX enhances T cell localization in previously hypoxic tumor areas, decreases Treg and increases activated cytotoxic T lymphocyte (CTL) accumulation. Specifically, OMX increased by 3-fold the Teff/Treg ratio, indicating a switch from an immunosuppressive to an immunopermissive microenvironment. These data have also been confirmed in subcutaneous immunocompetent tumor models. When combined with anti-PD-1, OMX increases CTL infiltration, proliferation and cytotoxic activity, and secretion of IFNg and IFNg-inducible cytokines. Furthermore, the combination of OMX with anti-PD-1 in late-stage GL261 tumor-bearing mice increases mouse survival by ~80%. The survival benefit observed with OMX could be predicted with circulating chemokines (post-hoc test).
By delivering oxygen specifically to the hypoxic tumor microenvironment, OMX may restore anti-cancer immune responses and synergize with immunotherapy to enhance tumor control and improve patient outcomes.