Background Evofosfamide (Evo) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard. It has been shown that targeting hypoxia with Evo improves T cell infiltration and cooperates with immune checkpoint blockade in mediating tumor regression in vivo.1 Moreover, in a phase 1 clinical trial, the combination of Evo with the anti-CTLA-4 Ipilimumab resulted in objective responses in patients with cold tumors.2 Here we tested Evo in combination with our novel dual-specific monoclonal antibody, IMGS-001. IMGS-001 targets PD-L1 and PD-L2 expressing cells and functions both through checkpoint blockade and inducing potent cell-mediated, antibody-dependent killing. We have shown that IMGS-001 remodels the tumor microenvironment by eliminating suppressor cells expressing PD-L1 and PD-L2.3 Here we assessed whether targeting hypoxia within the tumor with Evo would improve upon the responses observed in cold tumors treated with IMGS-001.
Methods In vivo anti-tumor efficacy was assessed using the B16F10 syngeneic mouse model of melanoma. B16F10 naturally expresses PD-L1 and for some studies was engineered to constitutively express mouse PD-L2. Tumor-bearing mice were treated with 50 mg/kg Evo and/or 10mg/kg IMGS-001 and/or 10mg/kg mouse anti-PD-1 RMP-1–14 twice per week, beginning three days after tumor implant. Mice were weighed and tumors were measured twice per week.
Results At 21 days post-tumor implant, all treatments had some negative effect on tumor growth, but only IMGS-001(p=0.0117) and Evo with IMGS-001(p=0.0047) reached statistical significance compared to PBS treatment. Treatment with IMGS-001 or the combination of Evo with IMGS-001 inhibited tumor growth by 87% and 94%, respectively. Adding anti-PD-1 clone RMP1–14 to Evo had no impact on efficacy or survival compared to Evo or anti-PD-1 alone. Evo with IMGS-001 significantly improved survival compared to the PBS (p=0.0008) and Evo with anti-PD-1 (p=0.0104) groups. At the end of the study, 60% of mice in the Evo with IMGS-001 group and 40% of the mice in the IMGS-001 group were alive and tumor-free, respectively, compared to 0 in the PBS and Evo treated groups and 10% in the Evo with anti-PD-1 and anti-PD-1 only groups.
Conclusions These data indicate that Evo and IMGS-001 in combination improves upon the efficacy of either treatment alone, and those improvements are not observed for Evo in combination with anti-PD-1 treatment. This novel combination treatment will continue to be tested in preclinical models and has potential to be tested in a clinical trial.
Acknowledgements This work was conducted with support from the Cancer Prevention and Research Institute of Texas (CPRIT).
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Hegde A, Jayaprakash P, Couillault CA, Piha-Paul S, Karp D, Rodon J, Pant S, Fu S, Dumbrava EE, Yap TA, Subbiah V, Bhosale P, Coarfa C, Higgins JP, Williams ET, Wilson TF, Lim J, Meric-Bernstam F, Sumner E, Zain H, Nguyen D, Nguyen LM, Rajapakshe K, Curran MA, Hong DS. A Phase I Dose-Escalation Study to Evaluate the Safety and Tolerability of Evofosfamide in Combination with Ipilimumab in Advanced Solid Malignancies. Clinical cancer research: an official journal of the American Association for Cancer Research, 2021;27(11):3050–3060.
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