Abstract 2790: Sensitizing the hypoxic tumor microenvironment with OMX, a breakthrough oxygen delivery protein: From protein engineering to clinical trial
Authors: Krtolica Ana , Le Moan Natacha , Leung Philberta , Seo Youngho , Winger Jonathan , Van Brocklin Henry , Kent Michael , Cary Stephen 
Published: July 2016

Hypoxia, or lack of oxygen, is a key modulator of the tumor microenvironment and is associated with immunosuppression, invasiveness, angiogenesis, radiotherapy resistance and poor patient outcomes. Methods to increase oxygen in the hypoxic tumor niche have failed due to the long distance oxygen must diffuse from dysfunctional vasculature to the hypoxic cells. To address this problem, we engineered OMX oxygen carriers that bind oxygen with high affinity and can specifically deliver oxygen to severely hypoxic tumor regions without afecting normoxic tissues. Here, we show that OMX extravasates through leaky tumor vasculature, penetrates into and delivers oxygen to hypoxic tumor tissue. This reduces hypoxia in the tumor microenvironment and sensitizes tumors to therapy. Specifically, OMX accumulation in tumors leads to an increase in tumor oxygenation in mouse human xenograft and immunocompetent rat orthotopic models, as assessed by direct oxygen measurement (oxygen probe), by18F-FMISO PET in vivo imaging and by IHC and ELISA assessment of hypoxia markers (pimonidazole, CAIX, CCI, HIF-1). Moreover, OMX-mediated tumor oxygenation increases efficacy of radiation therapy as demonstrated by ex-vivo clonogenic assay and tumor growth delay. Importantly, while radiation alone only moderately delays tumor growth, combination of OMX and radiation therapy leads to tumor eradication in &gt;50% of tumors. In addition to the enhancement of radiation therapy with OMX, we are currently exploring the capacity of OMX to ameliorate immunosuppressive microenvironment caused by hypoxia.

Results from a Phase 0 clinical trial in canine cancer patients indicate that OMX is well tolerated and safe to use in combination with standard of care radiation therapy even in aged and fragile canine patient populations. Similar to rodent tumor models, OMX penetrates the tumor tissue in spontaneous canine brain and melanoma tumors. Furthermore, OMX accumulation correlates with reduced hypoxia in the tumor microenvironment as assessed by multiple hypoxia markers using quantitative IHC and ELISA. Taken together, these preclinical safety and efficacy data in both rodents and canines strongly support our IND submission to initiate human clinical trials in newly diagnosed glioblastoma patients.

Results from completed and ongoing studies support the potential of OMX as modulator of hypoxic tumor microenvironment that may significantly impact the effectiveness of radiotherapy, chemotherapy and immunotherapy in a variety of solid tumors where hypoxia is major contributor to therapeutic resistance.

Citation Format: Ana Krtolica, Natacha Le Moan, Philberta Leung, Youngho Seo, Jonathan Winger, Henry Van Brocklin, Michael Kent, Stephen Cary. Sensitizing the hypoxic tumor microenvironment with OMX, a breakthrough oxygen delivery protein: From protein engineering to clinical trial. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2790.