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

Meenu Sharma, Hiep Khong, Faisal Fa’ak, Salah-Eddine Bentebibel, Louise M. E. Janssen, Brent C. Chesson, Caitlin A. Creasy, Marie-Andrée Forget, Laura Maria S. 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 Addepalli, Deborah H. Charych, Jonathan Zalevsky, Adi Diab and Willem W. Overwijk ()
Additional contact information
Meenu Sharma: University of Texas MD Anderson Cancer Center
Hiep Khong: University of Texas MD Anderson Cancer Center
Faisal Fa’ak: University of Texas MD Anderson Cancer Center
Salah-Eddine Bentebibel: University of Texas MD Anderson Cancer Center
Louise M. E. Janssen: University of Texas MD Anderson Cancer Center
Brent C. Chesson: University of Texas MD Anderson Cancer Center
Caitlin A. Creasy: University of Texas MD Anderson Cancer Center
Marie-Andrée Forget: University of Texas MD Anderson Cancer Center
Laura Maria S. Kahn: University of Texas MD Anderson Cancer Center
Barbara Pazdrak: University of Texas MD Anderson Cancer Center
Binisha Karki: University of Texas MD Anderson Cancer Center
Yared Hailemichael: University of Texas MD Anderson Cancer Center
Manisha Singh: University of Texas MD Anderson Cancer Center
Christina Vianden: University of Texas MD Anderson Cancer Center
Srinivas Vennam: Nektar Therapeutics
Uddalak Bharadwaj: The University of Texas MD Anderson Cancer Center
David J. Tweardy: The University of Texas MD Anderson Cancer Center
Cara Haymaker: University of Texas MD Anderson Cancer Center
Chantale Bernatchez: University of Texas MD Anderson Cancer Center
Shixia Huang: Baylor College of Medicine
Kimal Rajapakshe: Baylor College of Medicine
Cristian Coarfa: Baylor College of Medicine
Michael E. Hurwitz: Yale Comprehensive Cancer Center
Mario Sznol: Yale University Cancer Center, Yale University
Patrick Hwu: University of Texas MD Anderson Cancer Center
Ute Hoch: Nektar Therapeutics
Murali Addepalli: Nektar Therapeutics
Deborah H. Charych: Nektar Therapeutics
Jonathan Zalevsky: Nektar Therapeutics
Adi Diab: University of Texas MD Anderson Cancer Center
Willem W. Overwijk: University of Texas MD Anderson Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14471-1

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