705 Hypoxia-activated prodrugs with distinct mechanisms of action sensitize murine prostate tumors to immune checkpoint blockade

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Background Despite the success of immunotherapy in ‘hot’ tumors like melanoma with pre-existing immune infiltrates, ‘cold’ tumors like prostate cancer remain unresponsive.1–3 We identified that these tumors harbor regions of hypoxia that are islands of immune privilege excluding T cells, while retaining immune suppressive myeloid cells. Targeting hypoxia using the hypoxia-activated prodrug (HAP), evofosfamide (TH-302; IMGS-101) reduced hypoxic regions and co-operated with immune checkpoint blockade (ICB) (anti CTLA-4+anti PD-1) to drive tumor regression in transplantable and spontaneous murine prostate tumors.4 In a Phase I clinical trial, combination of evofosfamide and anti CTLA-4 (Ipilimumab) elicited both objective response and prolonged disease stabilization in patients who had failed other forms of therapy.5 While evofosfamide has shown promising results in preclinical and clinical settings, it is unknown whether hypoxia reduction is a unique property of evofosfamide or if HAP with distinct mechanisms of action could achieve comparable therapeutic efficacy. Methods We investigated the efficacy of evofosfamide, AQ4N (Banoxantrone) and TPZ (Tirapazamine), three HAP with distinct mechanisms of action, for their ability to reduce tumor hypoxia, drive tumor regression and sensitize murine prostate tumors to ICB. We used multi-parameter flow cytometry to characterize the immune composition of treated tumors, investigated the T cell dependence of their therapeutic efficacy and evaluated their impact on tumor metabolism, proliferation and viability. Results We identified evofosfamide and AQ4N to have monotherapy efficacy and reduce tumor burden in TRAMP-C2 tumor-bearing mice. While TPZ alone failed to have an effect, it improved responses to CTLA-4 blockade. Flow cytometry analyses of the tumor microenvironment (TME) revealed reversal of myeloid immune suppressive polarization and moderate improvements in CD8 and CD4 T effector proliferation. Depletion of CD8+ and CD4+ cells abrogated the therapeutic efficacy of HAP±αCTLA-4 therapies. Interestingly, 18F- FAZA PET imaging identified only Evofosfamide, but not AQ4N and TPZ, to be capable of major hypoxia reduction. In vitro metabolic and functional characterization of HAP treated tumors revealed enhanced cell death, reduced glucose uptake and mitochondrial membrane potential. Conclusions Our study highlights the relevance of tumor hypoxia as a source of immunotherapy resistance and identifies HAP, as a class of drugs capable of sensitizing cold tumors to ICB. We found that despite distinct mechanisms of action and apparently independent of their ability to suppress macroscopic tumor hypoxia, HAP influence diverse cell types in the TME by reducing tumor cell viability and metabolism, repolarizing immune suppressive myeloid stroma and promoting T cell function. References Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107(9):4275–80. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, doubleblind, phase 3 trial. Lancet Oncol. 2014;15(7):700–12. Jayaprakash P, Ai M, Liu A, Budhani P, Bartkowiak T, Sheng J, et al. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest. 2018;128 (11):5137–5149. Hegde A, Jayaprakash P, Couillault CA, Piha-Paul S, Karp D, Rodon J, et al. A phase I dose-escalation study to evaluate the safety and tolerability of evofosfamide in combination with ipilimumab in advanced solid malignancies. Clin Cancer Res. 2021;27(11):3050–3060. Ethics Approval All procedures were conducted in accordance with the guidelines established by the University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee.

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