Journal Article

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

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

2020

Overview

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. Interleukin-2 can induce an anti-tumour response, but is associated with toxicity. Here, the authors demonstrate that an engineered interleukin-2 promotes intratumoral T regulatory cell depletion while enhancing effective anti-tumour CD8 +  T cell responses that result in potent tumor suppression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/21 / 13/31 / 631/250/127 / 631/250/1619 / 631/250/251 / 631/67/1059 / 631/67/580 / Animals / Antibodies, Monoclonal, Humanized - administration & dosage / Anticancer properties / Antitumor agents / Cancer / Cancer therapies / Carcinoma, Renal Cell - drug therapy / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - immunology / CD122 antigen / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cohort Studies / CTLA-4 protein / Cytokines / Depletion / Drug Therapy, Combination / Female / Humanities and Social Sciences / Humans / Immune checkpoint / Immunoregulation / Interferon-gamma - genetics / Interferon-gamma - immunology / Interleukin 2 / Interleukin 2 receptors / Interleukin-2 - administration & dosage / Interleukin-2 - agonists / Interleukin-2 - analogs & derivatives / Interleukin-2 - immunology / Ipilimumab - administration & dosage / Kidney cancer / Lymphocyte Activation - drug effects / Lymphocytes / Lymphocytes T / Melanoma / Melanoma - drug therapy / Melanoma - genetics / Melanoma - immunology / Metastases / Mice / Mice, Inbred C57BL / multidisciplinary / PD-1 protein / Peptides / Polyethylene Glycols - administration & dosage / Prodrugs - administration & dosage / Receptors, Interleukin-2 - genetics / Receptors, Interleukin-2 - immunology / Renal cell carcinoma / Science / Science (multidisciplinary) / T-Lymphocytes, Regulatory - immunology / Therapy / Toxicity / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - immunology / Tumor necrosis factor-α / Tumor suppression / Tumors / Vaccination / γ-Interferon