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Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-14471-1

2041-1723

Meenu Sharma, Hiep Khong, Faisal Fa’ak, Salah-Eddine Bentebibel, Louise M.E. Janssen, Brent C. Chesson, Caitlin Creasy, Marie-Andrée Forget, Laura M. Kahn, Barbara Pazdrak, Binisha Karki, Yared Hailemichael, Manisha Singh, Christina Vianden, Srinivas Vennam, Uddalak Bharadwaj, David J. Tweardy, Cara Haymaker, Chantale Bernatchez, Shixia Huang, Kimal Rajapakshe, Cristian Coarfa, Michael E. Hurwitz, Mario Sznol, Patrick Hwu, Ute Hoch, Murali K. Addepalli, Deborah H. Charych, Jonathan Zalevsky, Adi Diab, Willem W. Overwijk,

Cancer Immunotherapy and Biomarkers

Abstract High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8 + T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8 + Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.