IMST-52. OMX, AN IND-STAGE BROAD-ACTING OXYGEN CARRIER, IMMUNOSENSITIZES THE TUMOR MICROENVIRONMENT AND PROMOTES EFFECTOR T CELL RESPONSES IN THE GL261 INTRACRANIAL SYNGENEIC GLIOBLASTOMA MODEL

Hypoxia, or lack of oxygen, is a hallmark of glioblastoma and is correlated with tumor progression and decreased overall survival. As a key modulator of the tumor microenvironment, hypoxia promotes immunosuppression through activation of multiple signaling pathways such as hypoxia-inducible factor/HIF signaling. OMX is an oxygen carrier biotherapeutic previously shown to: a) be well tolerated in small and large animals, b) efficiently accumulate in spontaneous canine brain tumors and rodent orthotopic glioblastoma (GL261 and F98), and c) significantly reduce hypoxia and improve radiotherapy efficacy in multiple tumor models. We immunohistochemically evaluated in GL261 model CD8+ (CTL) and CD4+ T lymphocyte infiltration into tumor areas that were hypoxic prior to treatment. We then characterized tumor infiltrating populations of NK cells, activated CTL (granzyme B+), and Treg (CD8+ FoxP3+) by flow cytometry in early and late stage GL261 tumors. Similar to previously published findings, we demonstrated CTLs are mostly excluded from hypoxic tumor areas in the GL261 model. Furthermore, a single OMX treatment in GL261 tumor-bearing mice reduces tumor hypoxia, enhances T cell localization in previously hypoxic tumor areas, and increases total CTL accumulation by ~4-fold. OMX treatment increased the activated CTL fraction by ~2 fold, while the immunosuppressive Treg fraction was reduced 2-fold. This resulted in a 3-fold increase of Teffector/Treg ratio, indicating a switch from an immunosupressive to an immunopermissive microenvironment. These data were confirmed in other subcutaneous tumor models. Results from ongoing OMX-checkpoint inhibitor combination survival studies are pending. By delivering oxygen specifically to the hypoxic tumor microenvironment, OMX may restore anti-cancer immune responses in glioblastoma patients. Given its good tolerability, dual mechanism of action as a radiation and immuno sensitizer, and broad multipathway activity, OMX may synergize with both radiotherapy and immuntherapy to enhance tumor control and improve patient outcomes.