| Autor: |
Sharma, Meenu, Khong, Hiep, Fa'ak, Faisal, Bentebibel, Salah-Eddine, Janssen, Louise M. E., Chesson, Brent C., Creasy, Caitlin A., Forget, Marie-Andrée, Kahn, Laura Maria S., Pazdrak, Barbara, Karki, Binisha, Hailemichael, Yared, Singh, Manisha, Vianden, Christina, Vennam, Srinivas, Bharadwaj, Uddalak, Tweardy, David J., Haymaker, Cara, Bernatchez, Chantale, Huang, Shixia |
| Předmět: |
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| Zdroj: |
Nature Communications; 1/31/2020, Vol. 11 Issue 1, p1-11, 11p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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