TY - JOUR
T1 - Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy
AU - Sharma, Meenu
AU - Khong, Hiep
AU - Fa’ak, Faisal
AU - Bentebibel, Salah Eddine
AU - Janssen, Louise M.E.
AU - Chesson, Brent C.
AU - Creasy, Caitlin A.
AU - Forget, Marie Andrée
AU - Kahn, Laura Maria S.
AU - Pazdrak, Barbara
AU - Karki, Binisha
AU - Hailemichael, Yared
AU - Singh, Manisha
AU - Vianden, Christina
AU - Vennam, Srinivas
AU - Bharadwaj, Uddalak
AU - Tweardy, David J.
AU - Haymaker, Cara
AU - Bernatchez, Chantale
AU - Huang, Shixia
AU - Rajapakshe, Kimal
AU - Coarfa, Cristian
AU - Hurwitz, Michael E.
AU - Sznol, Mario
AU - Hwu, Patrick
AU - Hoch, Ute
AU - Addepalli, Murali
AU - Charych, Deborah H.
AU - Zalevsky, Jonathan
AU - Diab, Adi
AU - Overwijk, Willem W.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85078824316
U2 - 10.1038/s41467-020-14471-1
DO - 10.1038/s41467-020-14471-1
M3 - Article
C2 - 32005826
AN - SCOPUS:85078824316
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 661
ER -