Abstract IA11: Reversal of immunotherapy resistance through hypoxia reduction

Across multiple cancers, we find that T cells fail to accumulate in regions of hypoxia that can occupy as much as 50% of the volume of some solid tumors. In mouse models of both prostate cancer and head and neck cancer, we find that the hypoxia-activated prodrug TH-302 (evofosfamide) can reduce hypoxia by triggering a tissue-remodeling process that culminates in revascularization with organized, functional vessels. In the TRAMP-C2 model of prostate cancer, combining TH-302 with blockade of the T-cell immune checkpoint receptors CTLA-4 and PD-1 cures nearly all mice of 7-day established tumors and the majority of larger, 2-week established malignancy. TRAMP transgenic mice, which do not respond at all to immunotherapy alone, treated with the combination of TH-302 and either CTLA-4 and PD-1 blockade or CTLA-4 blockade and 4-1BB agonist show exceptional tumor control at 36 weeks of age. Mechanistically, hypoxia favors accumulation of myeloid-derived suppressor cells (MDSC), and reduction of hypoxia using TH-302 significantly decreases both their frequency and density in prostate tumors. In addition, the capacity of MDSC from mice receiving hypoxia reduction and checkpoint blockade to suppress T-cell proliferation is significantly diminished. Tumor-infiltrating T cells benefit both directly and indirectly from hypoxia reduction as evidenced by increased proliferation, cytotoxicity, effector cytokine production, and survival. Immunofluorescence reveals a lack of T-cell infiltration of hypoxic zones even in the context of CTLA-4 and PD-1 blockade. In contrast, coadministration of TH-302 with checkpoint blockade promotes nearly equivalent T-cell densities across normoxic and hypoxic tumor areas. Clinically, we are evaluating the combination of TH-302 and ipilimumab in patients with checkpoint refractory melanoma, HPV- head and neck cancer, metastatic prostate cancer, and pancreatic cancer (NCT03098160). Correlative studies in these patients reveal advantageous skewing of the tumor immune microenvironment in tumors where hypoxia is reduced on therapy. Further studies of the response of patient cancers to this therapy are ongoing. In addition, we seek to understand the molecular mechanisms linking hypoxia to impaired suppression in stromal myeloid and fibroblast compartments, and to identify additional pharmacologic interventions capable of disrupting hypoxia. Citation Format: Priyamvada Jayaprakash, Midan Ai, Michael A. Curran. Reversal of immunotherapy resistance