Using syngeneic s.c. mouse models of 8 different tumor types, Sharma et al. showed that bempegaldesleukin, a long-lived IL-2 prodrug biased to bind IL-2Rβγ (over αβγ), enhanced checkpoint blockade- and peptide vaccine-promoted tumor regression. Probing T cell DNA/Vβ-Jβ usage, and responses of infused congenic tumor-specific T cells, showed that the drug systemically expanded CD8+ T cells and increased their intratumoral frequency/clonality. IFNγ and TNFα made by CD8+ T cells induced pro-apoptotic pathways to deplete intratumoral (only) Tregs. Similar intratumoral effects also trended in drug-treated patients with renal cell carcinoma and melanoma.
Contributed by Paula Hochman
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-2Rbeta). 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-gamma and TNF-alpha. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.
Author Info: (1) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Melanoma Medical Oncology, University of Texas MD An
Author Info: (1) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Nektar Therapeutics, 455 Mission Bay Blvd South, San Francisco, CA, USA. (16) Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. (17) Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. (18) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. Dan L. Duncan Cancer Center, Houston, TX, USA. (21) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. (22) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. (23) Yale Comprehensive Cancer Center, New Haven, CT, USA. (24) Yale University Cancer Center, Yale University, New Haven, CT, USA. (25) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Nektar Therapeutics, 455 Mission Bay Blvd South, San Francisco, CA, USA. (27) Nektar Therapeutics, 455 Mission Bay Blvd South, San Francisco, CA, USA. (28) Nektar Therapeutics, 455 Mission Bay Blvd South, San Francisco, CA, USA. (29) Nektar Therapeutics, 455 Mission Bay Blvd South, San Francisco, CA, USA. (30) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. woverwijk@nektar.com. Nektar Therapeutics, 455 Mission Bay Blvd South, San Francisco, CA, USA. woverwijk@nektar.com. The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, USA. woverwijk@nektar.com. Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. woverwijk@nektar.com.
