PEGylated IL-10 (Pegilodecakin) Induces Systemic Immune Activation, CD8 T Cell Invigoration and Polyclonal T Cell Expansion in Cancer Patients

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2018 Nov 14

PMID 30423297

Citations 119

Authors

Aung Naing

Jeffrey R Infante

Kyriakos P Papadopoulos

Ivan H Chan

Cong Shen

Navneet P Ratti

Bianca Rojo

Karen A Autio

Deborah J Wong

Manish R Patel

Patrick A Ott

Gerald S Falchook

Shubham Pant

Annie Hung

Kara L Pekarek

Victoria Wu

Matthew Adamow

Scott McCauley

John B Mumm

Phillip Wong

Peter Van Vlasselaer

Joseph Leveque

Nizar M Tannir

Martin Oft

Affiliations

Soon will be listed here.

Abstract

Tumor-reactive T cell exhaustion prevents the success of immune therapies. Pegilodecakin activates intratumoral CD8 T cells in mice and induces objective tumor responses in patients. Here we report that pegilodecakin induces hallmarks of CD8 T cell immunity in cancer patients, including elevation of interferon-γ and GranzymeB, expansion and activation of intratumoral CD8 T cells, and proliferation and expansion of LAG-3 PD-1 CD8 T cells. On pegilodecakin, newly expanded T cell clones, undetectable at baseline, become 1%-10% of the total T cell repertoire in the blood. Elevation of interleukin-18, expansion of LAG-3 PD-1 T cells and novel T cell clones each correlated with objective tumor responses. Combined pegilodecakin with anti-PD-1 increased the expansion of LAG-3 PD-1 CD8 T cells.

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References

Koppelman B, Neefjes J, De Vries J, de Waal Malefyt R . Interleukin-10 down-regulates MHC class II alphabeta peptide complexes at the plasma membrane of monocytes by affecting arrival and recycling. Immunity. 1998; 7(6):861-71. DOI: 10.1016/s1074-7613(00)80404-5. View

Gros A, Parkhurst M, Tran E, Pasetto A, Robbins P, Ilyas S . Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat Med. 2016; 22(4):433-8. PMC: 7446107. DOI: 10.1038/nm.4051. View

Heidema J, Rossen J, Lukens M, Ketel M, Scheltens E, Kranendonk M . Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold. J Immunol. 2008; 181(8):5551-9. DOI: 10.4049/jimmunol.181.8.5551. View

Naing A, Papadopoulos K, Autio K, Ott P, Patel M, Wong D . Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors. J Clin Oncol. 2016; 34(29):3562-3569. PMC: 5657013. DOI: 10.1200/JCO.2016.68.1106. View

Berg D, Davidson N, Kuhn R, Muller W, Menon S, Holland G . Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996; 98(4):1010-20. PMC: 507517. DOI: 10.1172/JCI118861. View

Rosenberg S, Dudley M . Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol. 2009; 21(2):233-40. PMC: 3459355. DOI: 10.1016/j.coi.2009.03.002. View

Im S, Hashimoto M, Gerner M, Lee J, Kissick H, Burger M . Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016; 537(7620):417-421. PMC: 5297183. DOI: 10.1038/nature19330. View

Knuth A, Wolfel T, Klehmann E, Boon T, Meyer zum Buschenfelde K . Cytolytic T-cell clones against an autologous human melanoma: specificity study and definition of three antigens by immunoselection. Proc Natl Acad Sci U S A. 1989; 86(8):2804-8. PMC: 287007. DOI: 10.1073/pnas.86.8.2804. View

Langowski J, Zhang X, Wu L, Mattson J, Chen T, Smith K . IL-23 promotes tumour incidence and growth. Nature. 2006; 442(7101):461-5. DOI: 10.1038/nature04808. View

10.

Emmerich J, Mumm J, Chan I, LaFace D, Truong H, Mcclanahan T . IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs. Cancer Res. 2012; 72(14):3570-81. DOI: 10.1158/0008-5472.CAN-12-0721. View

11.

Rizvi N, Hellmann M, Snyder A, Kvistborg P, Makarov V, Havel J . Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348(6230):124-8. PMC: 4993154. DOI: 10.1126/science.aaa1348. View

12.

Oft M . IL-10: master switch from tumor-promoting inflammation to antitumor immunity. Cancer Immunol Res. 2014; 2(3):194-9. DOI: 10.1158/2326-6066.CIR-13-0214. View

13.

Tran E, Ahmadzadeh M, Lu Y, Gros A, Turcotte S, Robbins P . Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015; 350(6266):1387-90. PMC: 7445892. DOI: 10.1126/science.aad1253. View

14.

Keir M, Butte M, Freeman G, Sharpe A . PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008; 26:677-704. PMC: 10637733. DOI: 10.1146/annurev.immunol.26.021607.090331. View

15.

Li W, Kashiwamura S, Ueda H, Sekiyama A, Okamura H . Protection of CD8+ T cells from activation-induced cell death by IL-18. J Leukoc Biol. 2007; 82(1):142-51. DOI: 10.1189/jlb.0706431. View

16.

Cohen C, Gartner J, Horovitz-Fried M, Shamalov K, Trebska-McGowan K, Bliskovsky V . Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J Clin Invest. 2015; 125(10):3981-91. PMC: 4607110. DOI: 10.1172/JCI82416. View

17.

MacNeil I, Suda T, Moore K, Mosmann T, Zlotnik A . IL-10, a novel growth cofactor for mature and immature T cells. J Immunol. 1990; 145(12):4167-73. View

18.

Mackall C, Fry T, Gress R . Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011; 11(5):330-42. PMC: 7351348. DOI: 10.1038/nri2970. View

19.

He X, Mahmood K, Maecker H, Holmes T, Kemble G, Arvin A . Analysis of the frequencies and of the memory T cell phenotypes of human CD8+ T cells specific for influenza A viruses. J Infect Dis. 2003; 187(7):1075-84. DOI: 10.1086/368218. View

20.

Langowski J, Kastelein R, Oft M . Swords into plowshares: IL-23 repurposes tumor immune surveillance. Trends Immunol. 2007; 28(5):207-12. DOI: 10.1016/j.it.2007.03.006. View