Sequential immunotherapy using an IL-2 receptor targeted fusion toxin followed by anti-PD-1 treatment inhibits B16 melanoma tumor growth in mice L.S. Cheung*, J. Fu*, G. Patrick, P. Kumar, C.K. Bullen, J.R. Murphy, D.M. Pardoll, W.R. Bishai Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD *participated equally
Background: Checkpoint inhibition immunotherapy, especially PD-1 blockade, has shown impressive clinical efficacy in the treatment of melanoma. Denileukin diftitox, DAB389IL-2, is a diphtheria fusion toxin approved for the treatment of cutaneous T cell lymphoma. DAB389IL-2 can transiently deplete regulatory T cells (Tregs) in vivo and has been found to induce tumor regression in patients with metastatic melanoma. We hypothesized that by depleting Tregs, DAB389IL-2 would inhibit B16 melanoma tumor growth and enhance the effector T cell response induced by anti-PD-1 treatment. Methods: C57BL/6 mice were injected subcutaneously with 1 x 105 B16F10 melanoma cells and treated with 5μg of DAB389IL-2 on d7 and d10 after tumor challenge. Anti-PD-1 was begun on d8 and dosed twice weekly. Tumor size was measured and flow cytometry was performed post-necropsy. Results: DAB389IL-2 inhibited B16 melanoma tumor growth and increased the frequency of IFNγ+ CD8+ tumor infiltrating lymphocytes (TILs). Sequential therapy with DAB389IL-2 followed by anti-PD-1 was superior to either single agent given alone, and increased the frequency of IFNγ+ TILs in tumors. We have also mutated a vascular leak inducing motif to construct DAB389IL-2(V6A). The V6A protein was as effective as the original fusion toxin in inhibiting B16 tumor growth, was better tolerated, caused substantially reduced vascular leak, and demonstrated less acute toxicity in mice. Conclusion: DAB389IL-2 exhibited potent in vivo anticancer activity both as a monotherapy and in sequential combination with anti-PD-1. DAB389IL-2(V6A) has similar potency but an improved safety profile and is in preclinical development as an anticancer treatment both as monotherapy and sequential combination therapy.
Funding: NIH AI 130595, Maryland TEDCO grant 0916-006
Credits
Credits: None available.
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