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853 Evofosfomide potentiates the efficacy of a novel anti-PD-L1/PD-L2 monoclonal antibody against immune excluded tumors
  1. Ahmad Salameh1,
  2. Paul Blezinger1,
  3. Christine Gagliardi1,
  4. Matt Hemberger1,
  5. James Barlow1,
  6. Michael Curran2 and
  7. Federica Pericle1
  1. 1ImmunoGenesis, Inc., Houston, TX, USA
  2. 2The University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


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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  2. 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.

  3. Salameh A, Pericle F, Gagliardi C, Blezinger P, Curran M. Preclinical characterization of IMGS-001, a dual antagonist anti-PD-L1 and PD-L2 antibody with effector function, to treat patients resistant to immune checkpoint blockade. JITC, 2022;10(2).

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