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Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.
- Source :
-
Nature communications [Nat Commun] 2020 Jan 31; Vol. 11 (1), pp. 661. Date of Electronic Publication: 2020 Jan 31. - Publication Year :
- 2020
-
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 <superscript>+</superscript> 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 <superscript>+</superscript> Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.
- Subjects :
- Animals
Antibodies, Monoclonal, Humanized administration & dosage
CD8-Positive T-Lymphocytes immunology
Carcinoma, Renal Cell genetics
Carcinoma, Renal Cell immunology
Cohort Studies
Drug Therapy, Combination
Female
Humans
Interferon-gamma genetics
Interferon-gamma immunology
Interleukin-2 administration & dosage
Interleukin-2 agonists
Interleukin-2 immunology
Ipilimumab administration & dosage
Lymphocyte Activation drug effects
Melanoma genetics
Melanoma immunology
Mice
Mice, Inbred C57BL
Receptors, Interleukin-2 genetics
Receptors, Interleukin-2 immunology
Tumor Necrosis Factor-alpha genetics
Tumor Necrosis Factor-alpha immunology
Carcinoma, Renal Cell drug therapy
Interleukin-2 analogs & derivatives
Melanoma drug therapy
Polyethylene Glycols administration & dosage
Prodrugs administration & dosage
T-Lymphocytes, Regulatory immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 32005826
- Full Text :
- https://doi.org/10.1038/s41467-020-14471-1