An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity.

Animals CD8-Positive T-Lymphocytes / immunology Cell Line, Tumor Colonic Neoplasms / immunology Disease Models, Animal Humans Immunotherapy Interleukin-15 / immunology Lymphocytes, Tumor-Infiltrating / immunology Melanoma, Experimental / immunology Mice Mice, Inbred BALB C Mice, Inbred C57BL Programmed Cell Death 1 Receptor / immunology Protein Engineering Recombinant Fusion Proteins / immunology

Journal

Cancer immunology research

ISSN: 2326-6074

Titre abrégé: Cancer Immunol Res

Pays: United States

ID NLM: 101614637

Informations de publication

Date de publication:
10 2021

Historique:

received: 24 01 2021

revised: 04 05 2021

accepted: 30 07 2021

pubmed: 12 8 2021

medline: 8 3 2022

entrez: 11 8 2021

Statut: ppublish

Résumé

The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused by excessive and systemic immune activation. Here, we set out to address these challenges by engineering a fusion protein of a single, potency-reduced, IL15 mutein and a PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed to deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation to PD1

Identifiants

DOI: 10.1158/2326-6066.CIR-21-0058 PMID: 34376502

pubmed: 34376502

pii: 2326-6066.CIR-21-0058

doi: 10.1158/2326-6066.CIR-21-0058

doi:

Substances chimiques

Interleukin-15 0

Programmed Cell Death 1 Receptor 0

Recombinant Fusion Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

1141-1157

Commentaires et corrections

Type : CommentIn

Informations de copyright

Références

Lee S, Margolin K. Cytokines in cancer immunotherapy. Cancers. 2011;3:3856–93.

Momin N, Mehta NK, Bennett NR, Ma L, Palmeri JR, Chinn MM, et al. Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy. Sci Transl Med. 2019;11:eaaw2614.

Tzeng A, Kwan BH, Opel CF, Navaratna T, Wittrup KD. Antigen specificity can be irrelevant to immunocytokine efficacy and biodistribution. Proc Natl Acad Sci U S A. 2015;112:3320–5.

Ring AM, Lin JX, Feng D, Mitra S, Rickert M, Bowman GR, et al. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat Immunol. 2012;13:1187–95.

Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res. 2015;3:219–27.

Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol. 2015;33:74–82.

Lentsch AB, Miller FN, Edwards MJ. Interleukin-2-induced hepatic injury involves temporal patterns of cell adhesion in the microcirculation. Am J Physiol. 1997;272:G727–31.

Schwartzentruber DJ. Guidelines for the safe administration of high-dose interleukin-2. J Immunother. 2001;24:287–93.

Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12:180–90.

Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol. 1991;9:694–704.

Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018;19:694–704.

Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rbetagamma-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 2019;9:711–21.

Sharma M, Khong H, Fa'ak F, Bentebibel SE, Janssen LME, Chesson BC, et al. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy. Nat Commun. 2020;11:661.

Kim KH, Kim HK, Kim HD, Kim CG, Lee H, Han JW, et al. PD-1 blockade-unresponsive human tumor-infiltrating CD8(+) T cells are marked by loss of CD28 expression and rescued by IL-15. Cell Mol Immunol. 2020;18:385–97.

Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, et al. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J Clin Invest. 2014;124:2246–59.

Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61.

Akinleye A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol. 2019;12:92.

Dubois S, Conlon KC, Müller JR, Hsu-Albert J, Beltran N, Bryant BR, et al. IL15 infusion of cancer patients expands the subpopulation of cytotoxic CD56(bright) NK cells and increases NK-cell cytokine release capabilities. Cancer Immunol Res. 2017;5:929–38.

Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer. 2014;2:3.

Fernandez-Poma SM, Salas-Benito D, Lozano T, Casares N, Riezu-Boj JI, Mancheño U, et al. Expansion of tumor-infiltrating CD8+ T cells expressing PD-1 improves the efficacy of adoptive T-cell therapy. Cancer Res. 2017;77:3672–84.

Besser MJ, Shapira-Frommer R, Schachter J. Tumor-infiltrating lymphocytes: clinical experience. Cancer J. 2015;21:465–9.

Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275–80.

Zhou G, Sprengers D, Boor PPC, Doukas M, Schutz H, Mancham S, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology. 2017;153:1107–1119.e10.

Myszka DG. Improving biosensor analysis. J Mol Recognit. 1999;12:279–84.

Hezareh M, Hessell AJ, Jensen RC, van de Winkel JG, Parren PW. Effector function activities of a panel of mutants of a broadly neutralizing antibody against human immunodeficiency virus type 1. J Virol. 2001;75:12161–8.

Schreeder DM, Cannon JP, Wu J, Li R, Shakhmatov MA, Davis RS. Cutting edge: FcR-like 6 is an MHC class II receptor. J Immunol. 2010;185:23–27.

Kobayashi H, Carrasquillo JA, Paik CH, Waldmann TA, Tagaya Y. Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15. Cancer Res. 2000;60:3577–83.

Fessas P, Lee H, Ikemizu S, Janowitz T. A molecular and preclinical comparison of the PD-1-targeted T-cell checkpoint inhibitors nivolumab and pembrolizumab. Semin Oncol. 2017;44:136–40.

Zhu X, Marcus WD, Xu W, Lee H-I, Han K, Egan JO, et al. Novel human interleukin-15 agonists. J Immunol. 2009;183:3598–607.

Rhode PR, Egan JO, Xu W, Hong H, Webb GM, Chen X, et al. Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models. Cancer Immunol Res. 2016;4:49–60.

Robinson TO, Schluns KS. The potential and promise of IL-15 in immuno-oncogenic therapies. Immunol Lett. 2017;190:159–68.

Fujii M, Sugamura K, Sano K, Nakai M, Sugita K, Hinuma Y. High-affinity receptor-mediated internalization and degradation of interleukin 2 in human T cells. J Exp Med. 1986;163:550–62.

Kumar A, Moreau JL, Gibert M, Theze J. Internalization of interleukin 2 (IL-2) by high affinity IL-2 receptors is required for the growth of IL-2-dependent T cell lines. J Immunol. 1987;139:3680–4.

Robb RJ, Greene WC. Internalization of interleukin 2 is mediated by the beta chain of the high-affinity interleukin 2 receptor. J Exp Med. 1987;165:1201–6.

Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 2019;20:326–36.

Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37.

Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537:417–21.

Hudson WH, Gensheimer J, Hashimoto M, Wieland A, Valanparambil RM, Li P, et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1(+) stem-like CD8(+) T cells during chronic infection. Immunity. 2019;51:1043–1058.

van der Leun AM, Thommen DS, Schumacher TN. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat Rev Cancer. 2020;20:218–32.

Chu T, Zehn D. Charting the roadmap of T cell exhaustion. Immunity. 2020;52:724–6.

Beltra J-C, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, et al. Developmental relationships of four exhausted CD8(+) T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity. 2020;52:825–841.

Zhou G, Noordam L, Sprengers D, Doukas M, Boor PPC, van Beek AA, et al. Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer. Oncoimmunology. 2018;7:e1448332.

Conlon KC, Miljkovic MD, Waldmann TA. Cytokines in the treatment of cancer. J Interferon Cytokine Res. 2019;39:6–21.

Valedkarimi Z, Nasiri H, Aghebati-Maleki L, Majidi J. Antibody-cytokine fusion proteins for improving efficacy and safety of cancer therapy. Biomed Pharmacother. 2017;95:731–42.

Neri D. Antibody-cytokine fusions: versatile products for the modulation of anticancer immunity. Cancer Immunol Res. 2019;7:348–54.

Young PA, Morrison SL, Timmerman JM. Antibody-cytokine fusion proteins for treatment of cancer: engineering cytokines for improved efficacy and safety. Semin Oncol. 2014;41:623–36.

Spangler JB, Moraga I, Mendoza JL, Garcia KC. Insights into cytokine-receptor interactions from cytokine engineering. Annu Rev Immunol. 2015;33:139–67.

Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res. 2016;22:680–90.

Pogue SL, Taura T, Bi M, Yun Y, Sho A, Mikesell G, et al. Targeting attenuated interferon-alpha to myeloma cells with a CD38 antibody induces potent tumor regression with reduced off-target activity. PLoS One. 2016;11:e0162472.

Klein C, Waldhauer I, Nicolini VG, Freimoser-Grundschober A, Nayak T, Vugts DJ, et al. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines. OncoImmunology. 2017;6:e1277306.

Vazquez-Lombardi R, Loetsch C, Zinkl D, Jackson J, Schofield P, Deenick EK, et al. Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells. Nat Commun. 2017;8:15373.

Moraga I, Spangler JB, Mendoza JL, Gakovic M, Wehrman TS, Krutzik P, et al. Synthekines are surrogate cytokine and growth factor agonists that compel signaling through non-natural receptor dimers. eLife. 2017;6:e22882.

Huyghe L, Van Parys A, Cauwels A, Van Lint S, De Munter S, Bultinck J, et al. Safe eradication of large established tumors using neovasculature-targeted tumor necrosis factor-based therapies. EMBO Mol Med. 2020;12:e11223.

Silva D-A, Yu S, Ulge UY, Spangler JB, Jude KM, Labão-Almeida C, et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature. 2019;565:186–91.

Sockolosky JT, Trotta E, Parisi G, Picton L, Su LL, Le AC, et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science. 2018;359:1037.

Shen S, Sckisel G, Sahoo A, Lalani A, Otter DD, Pearson J, et al. Engineered IL-21 cytokine muteins fused to anti-PD-1 antibodies can improve CD8+ T cell function and anti-tumor immunity. Front Immunol. 2020;11:832.

Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.

Margolin K, Morishima C, Velcheti V, Miller JS, Lee SM, Silk AW, et al. Phase I trial of ALT-803, a novel recombinant IL15 complex, in patients with advanced solid tumors. Clin Cancer Res. 2018;24:5552–61.

Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity. 2019;50:195–211.

Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 2017;545:60–65.