Hypoxia is pervasive across human cancer and its association with poor outcomes and aggressive malignant phenotypes has been increasingly appreciated. Previously, we and others described how T cells are virtually absent from hypoxic zones of tumors. Serendipitously, we discovered that the hypoxia-activated prodrug (HAP) TH-302 could potently reduce hypoxia in murine models of prostate, pancreatic and head and neck cancer. With this tool, we were able to test the hypothesis that reversal of hypoxia might restore T cell infiltration and improve sensitivity to T cell checkpoint blockade in “cold” tumors. Across both transplantable and spontaneous murine models of prostate cancer, we have shown that the combination of TH-302 and antibody blockade of CTLA-4 and PD-1 synergize in curing, regressing, or controlling these tumors. With our collaborator Dr. Hong, we launched a clinical trial of the combination of TH-302 (evofosfamide) and ipilimumab (αCTLA-4) in 2017 (NCT03098160) which has revealed the potential of this combination to regress established metastatic prostate and head and neck cancers in patients, and to significantly extend progression-free survival in late stage pancreatic cancer. While TH-302 can restore tumor oxygen supply, we have observed across multiple human and murine cancers that elevated oxygen metabolism (OxPhos) at the tumor cell level metabolically cripples T cells resulting in resistance to immunotherapy. Ongoing efforts in the lab are exploring mechanisms to selectively disable tumor oxygen hyper-metabolism, as well as alternative approaches to further dampen hypoxia in cancer.
1. Describe the impact of hypoxia on tumor immunity
2. Identify approaches for reducing tumor hypoxia
3. Describe the clinical impact of hypoxia reduction on sensitivity to CTLA-4 blockade