TMIC-15. OMX IS A TUMOR MICROENVIRONMENT MODIFIER THAT RESTORES ANTI-TUMOR IMMUNITY AND IMPROVES ANTI-TUMOR EFFICACY BY REDUCING TUMOR HYPOXIA IN INTRACRANIAL GLIOBLASTOMA MOUSE MODEL

Abstract BACKGROUND Intratumoral hypoxia is associated with resistance to chemo- and radio-therapies and poor patient outcomes. In addition, hypoxia promotes the immune escape of tumors by altering the recruitment and function of innate and adaptive immune effector and suppressor cells. Therefore, reversing tumor hypoxia to create an immunopermissive microenvironment may improve anti-tumor response, and combined with immunotherapy approaches such as checkpoint inhibitors (CPI) may increase therapeutic efficacy. OMX, an anti-cancer therapy designed to reverse tumor hypoxia, efficiently accumulates in orthotopic rodent GB and spontaneous canine brain tumors, reduces tumor hypoxia and enhances immunotherapeutic efficacy. METHODS We used in vivo bioluminescence imaging of tumor, immunohistochemistry, flow cytometry, and cytokine multiplex assays to evaluate OMX’s ability to immunosensitize the GL261 brain tumor microenvironment and promote tumor cures. RESULTS Following intravenous administration in brain tumor-bearing mice, OMX reduces tumor hypoxia, modulates the IFNg signaling pathway, enhances the infiltration of tumor-specific CX3CR1+ CD8 T cells into the tumor (using the EphA2 as a GL261-specific tumor antigen), increases the activation of cytotoxic T lymphocytes (CTLs), decreases Tim3 and Lag3 exhaustion markers on CD8 T cells, and reduces the number of immunosuppressive cells such as MDSCs and Tregs in the tumor. Similar immunological changes are observed when OMX is combined with anti-PD-1. In late-stage 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 injected on the other side of the brain, all mice treated with the combination of OMX with anti-PD-1 survived, indicating the presence of long-term immunological memory against glioma cells. CONCLUSION By delivering oxygen specifically to the hypoxic tumor microenvironment, OMX may restore anti-cancer immune responses in GB patients and synergize with radiotherapy and immunotherapy to enhance tumor control and improve patient outcomes.