Immunosensitization of the hypoxic tumor microenvironment by the oxygen carrier OMX leads to tumor cures in mouse models of intracranial glioblastoma and advanced colitis-associated colon cancer Natacha Le Moan1*, Kevin Leong1*, Yuqiong Pan1, Sarah Ng1, Tina Davis1, Changan Guo1, Padmini Narayanan1, Jonathan Winger1, Stephen P.L. Cary1 and Ana Krtolica1 1Omniox Inc., 75 Shoreway, Suite B, San Carlos, CA 94070, USA *Authors contributed equally
Hypoxia, a common feature in solid tumors, is associated with resistance to chemo- and radio-therapies and poor patient outcomes. In addition, hypoxia promotes immune tolerance by altering the recruitment and function of innate and adaptive immune effector and suppressor cells. Therefore, reversing tumor hypoxia to create an immunopermissive microenvironment can improve anti-tumor response, and combined with immunotherapy approaches such as checkpoint inhibitors (CPI) may increase therapeutic efficacy. We have previously demonstrated that (i) OMX is well tolerated in small (rats and mice) and large (sheep and dogs) animals, (ii) hypoxia generates an immunosuppressive tumor microenvironment that limits effector T cell infiltration, (iii) OMX extravasates through leaky tumor vasculature and efficiently accumulates in orthotopic rodent and spontaneous canine tumors to reverse tumor hypoxia, and (iv) OMX promotes effector T cell infiltration and reduces Treg cells resulting in greater tumor control. Here, we used live tumor imaging, immunohistochemistry, flow cytometry, and multiplex cytokine assays to evaluate OMX's ability to immunosensitize the tumor microenvironment and promote tumor cures in chemically induced mouse model of colitis-associated colon cancer (CAC) and intracranial GL261 glioblastoma mouse tumor model. More precisely, OMX decreases presence of Tregs in the tumors, increases tumor-specific CX3CR1+ CD8 T cell infiltration, augments CTLs proliferation and cytotoxic activity, reduces CD8 T cell exhaustion, and modulates IFNg and IFNg-inducible cytokines that polarize T cells towards a Th1 phenotype. We show that OMX single agent treatment exhibits anti-tumor efficacy in advanced CAC tumors by reducing CAC tumor number and total CAC tumor burden, and reversing colon length shortening. Furthermore, in late-stage GL261 tumor-bearing mice, we observed a ~40% tumor cure rate for the combination of OMX with anti-PD-1, while anti-PD-1 alone resulted only in 5% tumor cures. Following rechallenge with GL261 tumor cells, all mice treated with OMX survived, indicating the presence of long-term immunological memory against glioma cells. Taken together, our data in orthotopic glioblastoma and colon cancer mouse models suggest that by delivering oxygen to hypoxic tumor regions, OMX immunosensitizes tumor microenvironment, leading to tumor responses and cures. Therefore, OMX may restore anti-cancer immune responses in cancer patients and synergize with radiotherapy and immunotherapy to enhance tumor control and improve patient outcomes.
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