Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32005826.
- Also identified by DOI 10.1038/s41467-020-14471-1 and PMC identifier 6994577.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sup>+</sup> 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<sup>+</sup> Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies.
Medical subject headings
- Carcinoma, Renal Cell
- Interleukin-2
- Melanoma
- Polyethylene Glycols
- Prodrugs
- T-Lymphocytes, Regulatory