Preexisting Autoimmune Disease: Implications for Immune Checkpoint Inhibitor Therapy in Solid Tumors

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  • a Department of Medicine, Division of Oncology, University of Washington, and
  • b Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
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The use of immune checkpoint inhibitors (ICIs) is rapidly expanding to the treatment of many cancer types, both in the metastatic setting and as an adjuvant to other therapies. Clinical trials using ICIs have largely excluded patients with preexisting autoimmune diseases due to concerns for increased toxicity. However, emerging evidence shows that ICIs may be considered in some patients with autoimmunity. This review discusses the commonalities between clinical autoimmune diseases and ICI-induced immunotherapy-related adverse events, and summarizes the existing case series that describes patients with solid tumors who have a preexisting autoimmune disease. This review also discusses which patients with autoimmunity could be considered reasonable candidates for ICI therapy.

Submitted December 21, 2018; accepted for publication April 12, 2019.

Disclosures: Dr. Bhatia has disclosed that he serves on the scientific advisory board for EMD-Serono, Sanofi-Genzyme, and Bristol-Myers Squibb, and that he receives grant/research support from EMD-Serono, Merck & Co., Inc., Bristol-Myers Squibb, NantKwest, Novartis, and Immune Design. Dr. Grivas has disclosed that he has received consulting fees/honoraria from Bayer, Merck & Co., Pfizer, Bristol-Myers Squibb, AstraZeneca, Clovis Oncology, EMD Serono, Driver Inc., QED Therapeutics, Heron Therapeutics, and Janssen, and he has received grant/research support from AstraZeneca, Pfizer, Clovis Oncology, Bavarian Nordic, and Immunomedics. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Petros Grivas, MD, PhD, Department of Medicine, Division of Oncology, University of Washington, 825 Eastlake Avenue East, G-4830, Seattle, WA 98109. Email: pgrivas@uw.edu
  • 1.

    Thommen DS, Schumacher TN. T cell dysfunction in cancer. Cancer Cell 2018;33:547562.

  • 2.

    Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis 2015;6:e1792.

  • 3.

    Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood 2018;131:5867.

  • 4.

    Davids MS, Kim HT, Bachireddy P, . Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med 2016;375:143153.

  • 5.

    Lo JA, Fisher DE, Flaherty KT. Prognostic significance of cutaneous adverse events associated with pembrolizumab therapy. JAMA Oncol 2015;1:13401341.

  • 6.

    Freeman-Keller M, Kim Y, Cronin H, . Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 2016;22:886894.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Santini FC, Rizvi H, Plodkowski AJ, . Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res 2018;6:10931099.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Brahmer JR, Lacchetti C, Schneider BJ, . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2018;36:17141768.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Puzanov I, Diab A, Abdallah K, . Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5:95.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Anquetil C, Salem JE, Lebrun-Vignes B, . Immune checkpoint inhibitor-associated myositis. Circulation 2018;138:743745.

  • 11.

    Cuzzubbo S, Javeri F, Tissier M, . Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer 2017;73:18.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Thompson JA, Schneider BJ, Brahmer J, . NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities, Version 1.2019. To view the most recent version, visit NCCN.org. J Natl Compr Canc Netw 2019;17:255289.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Michot JM, Bigenwald C, Champiat S, . Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139148.

  • 14.

    Zamani MR, Aslani S, Salmaninejad A, . PD-1/PD-L and autoimmunity: a growing relationship. Cell Immunol 2016;310:2741.

  • 15.

    Chaouali M, Carvalho A, Tezeghdenti A, . Cytotoxic T lymphocyte antigen-4 gene polymorphisms and susceptibility to type 1 autoimmune hepatitis in the Tunisian population. Genes Dis 2017;5:256262.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Fang M, Huang W, Mo D, . Association of five SNPs in cytotoxic T-lymphocyte antigen 4 and cancer susceptibility: evidence from 67 studies. Cell Physiol Biochem 2018;47:414427.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Ramzi M, Arandi N, Saadi MI, . Genetic variation of costimulatory molecules, including cytotoxic T-lymphocyte antigen 4, inducible T-cell costimulator, cluster differentiation 28, and programmed cell death 1 genes, in Iranian patients with leukemia [published online April 26, 2018]. Exp Clin Transplant. doi: 10.6002/ect.2017.0176

    • Search Google Scholar
    • Export Citation
  • 18.

    Karabon L, Markiewicz M, Chrobot K, . The influence of genetic variations in the CD86 gene on the outcome after allogeneic hematopoietic stem cell transplantation. J Immunol Res 2018;2018:3826989.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Fouad NA, Saeed AM, Mahedy AW. Association of CTLA-4 +49 A/G and CT60 gene polymorphism with Graves’ disease. Egypt J Immunol 2017;24:6370.

  • 20.

    Santos N, Rodríguez-Romanos R, de la Cámara R, . PD-1 genotype of the donor is associated with acute graft-versus-host disease after HLA-identical sibling donor stem cell transplantation. Ann Hematol 2018;97:22172224.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Zou Y, Zhang Z, Liu Y, . Are programmed cell death 1 gene polymorphisms correlated with susceptibility to rheumatoid arthritis?: a meta-analysis. Medicine (Baltimore) 2017;96:e7805.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Gao J, Shi LZ, Zhao H, . Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 2016;167:397404.e9.

  • 23.

    Joseph S, George NI, Green-Knox B, . Epigenome-wide association study of peripheral blood mononuclear cells in systemic lupus erythematosus: identifying DNA methylation signatures associated with interferon-related genes based on ethnicity and SLEDAI. J Autoimmun 2019;96:147157.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Kowanetz M, Zou W, Gettinger SN, . Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1). Proc Natl Acad Sci USA 2018;115:E1011910126.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Caturegli P, Di Dalmazi G, Lombardi M, . Hypophysitis secondary to cytotoxic T-lymphocyte-associated protein 4 blockade: insights into pathogenesis from an autopsy series. Am J Pathol 2016;186:32253235.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Iwama S, De Remigis A, Callahan MK, . Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med 2014;6:230ra45.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Osorio JC, Ni A, Chaft JE, . Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol 2017;28:583589.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Byrne EH, Fisher DE. Immune and molecular correlates in melanoma treated with immune checkpoint blockade. Cancer 2017;123:21432153.

  • 29.

    Johnson DB, Balko JM, Compton ML, . Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:17491755.

  • 30.

    Borghaei H, Paz-Ares L, Horn L, . Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 2015;373:16271639.

  • 31.

    Wolchok JD, Chiarion-Sileni V, Gonzalez R, . Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377:13451356.

  • 32.

    Robert C, Schachter J, Long GV, . Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:25212532.

  • 33.

    Reck M, Rodríguez-Abreu D, Robinson AG, . Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:18231833.

  • 34.

    Rittmeyer A, Barlesi F, Waterkamp D, . Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255265.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Motzer RJ, Escudier B, McDermott DF, . Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:18031813.

  • 36.

    Powles T, Durán I, van der Heijden MS, . Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2018;391:748757.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Bellmunt J, de Wit R, Vaughn DJ, . Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:10151026.

  • 38.

    Motzer RJ, Tannir NM, McDermott DF, . Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:12771290.

  • 39.

    Wang DY, Salem JE, Cohen JV, . Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018;4:17211728.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Tison A, Quere G, Misery L, . OP0196 safety and efficacy of immune checkpoint inhibitors in patients with cancer and preexisting autoimmune diseases: a nationwide multicenter retrospective study [abstract]. Ann Rheum Dis 2018;77:Abstract 147.

    • Search Google Scholar
    • Export Citation
  • 41.

    Leonardi GC, Gainor JF, Altan M, . Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. J Clin Oncol 2018;36:19051912.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Menzies AM, Johnson DB, Ramanujam S, . Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol 2017;28:368376.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Danlos FX, Voisin AL, Dyevre V, . Safety and efficacy of anti-programmed death 1 antibodies in patients with cancer and pre-existing autoimmune or inflammatory disease. Eur J Cancer 2018;91:2129.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Johnson DB, Sullivan RJ, Ott PA, . Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol 2016;2:234240.

  • 45.

    Gutzmer R, Koop A, Meier F, . Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Eur J Cancer 2017;75:2432.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Richter MD, Pinkston O, Kottschade LA, . Brief report: cancer immunotherapy in patients with preexisting rheumatic disease: the Mayo Clinic experience. Arthritis Rheumatol 2018;70:356360.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    Lee B, Wong A, Kee D, . The use of ipilimumab in patients with rheumatoid arthritis and metastatic melanoma. Ann Oncol 2016;27:11741177.

  • 48.

    Mitsune A, Yanagisawa S, Fukuhara T, . Relapsed myasthenia gravis after nivolumab treatment. Intern Med 2018;57:18931897.

  • 49.

    Derle E, Benli S. Ipilimumab treatment associated with myasthenic crises and unfavorable disease course. Neurol Sci 2018;39:17731774.

  • 50.

    Cooper DS, Meriggioli MN, Bonomi PD, . Severe exacerbation of myasthenia gravis associated with checkpoint inhibitor immunotherapy. J Neuromuscul Dis 2017;4:169173.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Arbour KC, Mezquita L, Long N, . Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2018;36:28722878.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Horvat TZ, Adel NG, Dang TO, . Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol 2015;33:31933198.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Eggermont AM, Blank CU, Mandala M, . Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 2018;378:17891801.

  • 54.

    Bergqvist V, Hertervig E, Gedeon P, . Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol Immunother 2017;66:581592.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 55.

    Antonia SJ, Villegas A, Daniel D, . Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017;377:19191929.

  • 56.

    Weber J, Mandala M, Del Vecchio M, . Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:18241835.

  • 57.

    Warren EH, Deeg HJ. Dissecting graft-versus-leukemia from graft-versus-host-disease using novel strategies. Tissue Antigens 2013;81:183193.

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