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

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

doi:10.1038/s41467-020-14471-1

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

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

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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⁺ 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.

Original language	English (US)
Article number	661
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14471-1
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Sharma, M., Khong, H., Fa’ak, F., Bentebibel, S. E., Janssen, L. M. E., Chesson, B. C., Creasy, C. A., Forget, M. A., Kahn, L. M. S., Pazdrak, B., Karki, B., Hailemichael, Y., Singh, M., Vianden, C., Vennam, S., Bharadwaj, U., Tweardy, D. J., Haymaker, C., Bernatchez, C., ... Overwijk, W. W. (2020). Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy. Nature communications, 11(1), Article 661. https://doi.org/10.1038/s41467-020-14471-1

Sharma, M, Khong, H, Fa’ak, F, Bentebibel, SE, Janssen, LME, Chesson, BC, Creasy, CA, Forget, MA, Kahn, LMS, Pazdrak, B, Karki, B, Hailemichael, Y , Singh, M, Vianden, C, Vennam, S, Bharadwaj, U , Tweardy, DJ , Haymaker, C, Bernatchez, C, Huang, S, Rajapakshe, K, Coarfa, C, Hurwitz, ME, Sznol, M, Hwu, P, Hoch, U, Addepalli, M, Charych, DH, Zalevsky, J, Diab, A & Overwijk, WW 2020, 'Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy', Nature communications, vol. 11, no. 1, 661. https://doi.org/10.1038/s41467-020-14471-1

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title = "Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy",

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+ 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.",

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

note = "Funding Information: This work was supported in part by Cancer Prevention & Research Institute of Texas Proteomics & Metabolomics Core Facility Support Award (RP170005) (S.H., C.C., K.R.) and NCI Cancer Center Support Grant to Antibody-based Proteomics Core/Shared Resource (P30CA125123) (S.H., C.C.) and NIEHS P30 Center grant 1P30ES030285 (C.C.) and a research grant from Nektar Therapeutics to W.W.O./MDACC and A.D./ MDACC. We thank Ms. Fuli Jia, Weiyu Jiang, and Dr. Danli Wu from the Antibody-based Proteomics Core/Shared Resource for their excellent technical assistance in performing RPPA experiments. MD Anderson cancer center (MDACC) flow cytometry and cell-sorting core (south campus) is supported by NCI P30CA016672. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

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doi = "10.1038/s41467-020-14471-1",

language = "English (US)",

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journal = "Nature communications",

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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 - Funding Information: This work was supported in part by Cancer Prevention & Research Institute of Texas Proteomics & Metabolomics Core Facility Support Award (RP170005) (S.H., C.C., K.R.) and NCI Cancer Center Support Grant to Antibody-based Proteomics Core/Shared Resource (P30CA125123) (S.H., C.C.) and NIEHS P30 Center grant 1P30ES030285 (C.C.) and a research grant from Nektar Therapeutics to W.W.O./MDACC and A.D./ MDACC. We thank Ms. Fuli Jia, Weiyu Jiang, and Dr. Danli Wu from the Antibody-based Proteomics Core/Shared Resource for their excellent technical assistance in performing RPPA experiments. MD Anderson cancer center (MDACC) flow cytometry and cell-sorting core (south campus) is supported by NCI P30CA016672. 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.

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SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 661

ER -

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

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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