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Endocrine and metabolic adverse effects of immune checkpoint inhibitors: an overview (what endocrinologists should know)

  • R. M. Ruggeri
  • A. Campennì
  • G. GiuffridaEmail author
  • P. Trimboli
  • L. Giovanella
  • F. Trimarchi
  • S. Cannavò
Review Article

Abstract

Immune checkpoint inhibitors (ICIs) are novel anticancer agents, recently introduced with the aim of boosting the immune response against tumors. ICIs are monoclonal autoantibodies that specifically target inhibitory receptors on T cells: cytotoxic T lymphocyte antigen 4 (CTLA4), programmed death 1 (PD-1) and its ligand (PD-1L). ICIs also generate peculiar dysimmune toxicities, called immune-related adverse events (irAEs), that can potentially affect any tissue, and some may be life-threatening if not promptly recognized. The endocrine and metabolic side effects of ICIs are reviewed here, with a particular focus on their clinical presentation and management. They are among the most frequent toxicities (around 10%) and include hypophysitis, thyroid disorders, adrenalitis, and diabetes mellitus. Treatment is based on the replacement of specific hormone deficits, accompanied by immunosuppression (with corticosteroids or other drugs), depending on irAEs grade, often without the need of ICI withdrawal, except in more severe forms. Prompt recognition of endocrine and metabolic irAEs and adequate treatment allow the patients to continue a therapy they are benefiting from. Endocrinologists, as an integral part of the multidisciplinary oncologic team, need to be familiar with the unique toxicity profile of these anticancer agents. Practical recommendations for their management are proposed.

Keywords

Immune checkpoint inhibitors Cancer treatment Endocrine side effects CTLA4 PD1/PD1-L Thyroid diseases Hypophysitis Hyponatremia 

Notes

Funding

This research did not receive any specific Grant from any funding agency in the public, commercial or not-for-profit sector.

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent is not required.

References

  1. 1.
    Dillman RO (2011) Cancer immunotherapy. Cancer Biother Radiopharm 26:1–64CrossRefGoogle Scholar
  2. 2.
    Stewart TJ, Smyth MJ (2011) Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metast Rev 30:125–140CrossRefGoogle Scholar
  3. 3.
    Kim R, Emi M, Tanabe K (2007) Cancer immunoediting from immune surveillance to immune escape. Immunology 121:1–14CrossRefGoogle Scholar
  4. 4.
    Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Intern Immunol 8:765–772CrossRefGoogle Scholar
  5. 5.
    Wang XB, Zheng CY, Giscombe R, Lefvert AK (2001) Regulation of surface and intracellular expression of CTLA4 oh human peripheral T cells. Scand J Immunol 54:453–458CrossRefGoogle Scholar
  6. 6.
    Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33:1974–1982CrossRefGoogle Scholar
  7. 7.
    Hargadon KM, Johnson CE, Williams CJ (2018) Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol 62:29–39.  https://doi.org/10.1016/j.intimp.2018.06.001 CrossRefPubMedGoogle Scholar
  8. 8.
    Puzanov I, Diab A, Abdallah K, Bingham CO III, Brogdon C, Dadu R, Hamad L, Kim S, Lacouture ME, LeBoeuf NR, Society for Immunotherapy of Cancer Toxicity Management Working Group et al (2017) Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 5:95.  https://doi.org/10.1186/s40425-017-0300-z CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ryder M, Callahan M, Postow M, Wolchok J, Fagin JA (2014) Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer 21:371–381CrossRefGoogle Scholar
  10. 10.
    Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, Gutzmer R, Utikal JS, Göppner D et al (2016) Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 60:190–209CrossRefGoogle Scholar
  11. 11.
    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM et al (2016) Prolonged survival in stage III Melanoma with Ipilimumab adjuvant therapy. N Engl J Med 375:1845–1855CrossRefGoogle Scholar
  12. 12.
    US Department of Health and Human Services NIoH, National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Bethesda, Md, 2010. [updated (v4.03: June 14, 2010) May 28, 2009]. NIH publication no. 90-5410Google Scholar
  13. 13.
    Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R, Hollebecque A et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148CrossRefGoogle Scholar
  14. 14.
    Horvat TZ, Adel NG, Dang TO, Momtaz P, Postow MA, Callahan MK, Carvajal RD, Dickson MA, D’Angelo SP, Woo KM et al (2015) 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 33:3193–3198CrossRefGoogle Scholar
  15. 15.
    Herbst RS, Baas P, Kim D, Felip E, Pérez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540–1550CrossRefGoogle Scholar
  16. 16.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23–34CrossRefGoogle Scholar
  17. 17.
    Abdel-Wahab N, Shah M, Lopez-Olivo MA, Suarez-Almazor ME (2018) Use of immune checkpoint inhibitors in the treatment of patients with cancer and pre-existing autoimmune disease. Ann Intern Med 169:133–134.  https://doi.org/10.7326/L18-0209 CrossRefPubMedGoogle Scholar
  18. 18.
    Eigentler TK, Hassel JC, Berking C, Aberle J, Bachmann O, Grünwald V, Kähler KC, Loquai C, Reinmuth N, Steins M et al (2016) Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD1 antibody therapy. Cancer Treat Rev 45:7–18CrossRefGoogle Scholar
  19. 19.
    Joshi MN, Whitelaw BC, Palomar MTP, Wu Y, Carroll PV (2016) Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction. Clin Endocrinol 85:331–339CrossRefGoogle Scholar
  20. 20.
    Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FS, MDX010-20 Investigators (2013) Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 119:1675–1682CrossRefGoogle Scholar
  21. 21.
    Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2354–2443CrossRefGoogle Scholar
  22. 22.
    Guaraldi F, La Selva R, Samà MT, D’Angelo V, Gori D, Fava P, Fierro MT, Savoia P, Arvat E (2018) Characterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution. J Endocrinol Invest 41:549–556.  https://doi.org/10.1007/s40618-017-0772-1 CrossRefPubMedGoogle Scholar
  23. 23.
    Faje AT, Sullivan R, Lawrence D, Tritos NA, Fadden R, Klibanski A, Nachtigall L et al (2014) Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J Clin Endocrinol Metab 99:4078–4085CrossRefGoogle Scholar
  24. 24.
    Araujo PB, Coelho MC, Arruda M, Gadelha MR, Neto LV (2015) Ipilimumab-induced hypophysitis: review of the literature. J Endocrinol Invest 38:1159–1166.  https://doi.org/10.1007/s40618-015-0301-z CrossRefPubMedGoogle Scholar
  25. 25.
    Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F (2013) Endocrine side-effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 98:1361–1375CrossRefGoogle Scholar
  26. 26.
    Marlier J, Cocquyt V, Brochez L, Van Belle S, Kruse V (2014) Ipilimumab, not just another anti-cancer therapy: hypophysitis as side effect illustrated by four case-reports. Endocrine 47:878–883CrossRefGoogle Scholar
  27. 27.
    Dillard T, Yedinak CG, Alumkal J, Fleseriu M (2010) Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 13:29–38CrossRefGoogle Scholar
  28. 28.
    Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, Kammula US, Royal RE, Topalian SL, Haworth LR, Levy C et al (2005) Cytotoxic T lymphocyte associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 28:593–598CrossRefGoogle Scholar
  29. 29.
    Carpenter KJ, Murtagh RD, Lilienfeld H, Weber J, Murtagh FR (2009) Ipilimumab-induced hypophysitis: MR imaging findings. Am J Neuroradiol 30:1751–1753CrossRefGoogle Scholar
  30. 30.
    Chalan P, Di Dalmazi G, Pani F, De Remigis A, Corsello A, Caturegli P (2018) Thyroid dysfunctions secondary to cancer immunotherapy. J Endocrinol Invest 41:625–638.  https://doi.org/10.1007/s40618-017-0778-8 CrossRefPubMedGoogle Scholar
  31. 31.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M et al (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 19:372(26)Google Scholar
  32. 32.
    O’Malley G, Lee HJ, Parekh S, Galsky MD, Smith CB, Friedlander P, Yanagisawa RT, Gallagher EJ (2017) Rapid evolution of thyroid dysfunction in patients treated with nivolumab. Endocr Pract 23:1223–1231CrossRefGoogle Scholar
  33. 33.
    Orlov S, Salari F, Kashat L, Walfish PG (2015) Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J Clin Endocrinol Metab 100:1738–1741CrossRefGoogle Scholar
  34. 34.
    Yamauchi I, Sakane Y, Fukuda Y, Fujii T, Taura D, Hirata M, Hirota K, Ueda Y, Kanai Y, Yamashita Y et al (2017) Clinical features of nivolumab-induced thyroiditis: a case series study. Thyroid 27:894–901CrossRefGoogle Scholar
  35. 35.
    Giuffrida G, Campennì A, Trimarchi F, Ruggeri RM (2017) Thyroid dysfunction in patients treated with the immune checkpoint inhibitor nivolumab: different clinical features. APMB 105(2):A2 (1–6).  https://doi.org/10.6092/1828-6550/apmb.105.2.2017.a2 CrossRefGoogle Scholar
  36. 36.
    Min L, Vaidya A, Becker C (2011) Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol 164:303–307CrossRefGoogle Scholar
  37. 37.
    Sabini E, Sframeli A, Marinò M (2018) A case of drug-induced Graves’ orbitopathy after combination therapy with Tremelimumab and Durvalumab. J Endocrinol Invest 41(7):877–878.  https://doi.org/10.1007/s40618-018-0906-0 (Epub 26 May 2018) CrossRefPubMedGoogle Scholar
  38. 38.
    Carl D, Grullich C, Hering S, Schabet M (2015) Steroid responsive encephalopathy associated with autoimmune thyroiditis following ipilimumab therapy: a case report. BMC Res Notes 8:316CrossRefGoogle Scholar
  39. 39.
    McMillen B, Dhillon, Yong-Yow S (2016) A rare case of thyroid storm. BMJ Case Rep.  https://doi.org/10.1136/bcr-2016-214603 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Khan U, Rizvi H, Sano D, Chiu J, Hadid T (2017) Nivolumab induced myxedema crisis. J Immunother Cancer 5:13CrossRefGoogle Scholar
  41. 41.
    Min L, Ibrahim N (2013) Ipilimumab-induced autoimmune andrenalitis. Lancet Diabetes Endocrinol 1:15CrossRefGoogle Scholar
  42. 42.
    Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, van der Veer S, Van Biesen W, Nagler E, Hyponatraemia Guideline Development Group (2014) Clinical practice guideline on diagnosis and treatment of hyponatraemia. Eur J Endocrinol 170:G1–47.  https://doi.org/10.1530/EJE-13-1020 CrossRefPubMedGoogle Scholar
  43. 43.
    Howard SA, Krajewski KM, Jagannathan JP, Braschi-Amirfarzan M, Tirumani SH, Shinagare AB, Ramaiya NH (2016) A new look at toxicity in the era of precision oncology: imaging findings, their relationship with tumor response, and effect on metastasectomy. Am J Roentgenol 207:4–14.  https://doi.org/10.2214/AJR.15.15480 CrossRefGoogle Scholar
  44. 44.
    Bacanovic S, Burger IA, Stolzmann P, Hafner J, Huellner MW (2015) Ipilimumab-induced adrenalitis: a possible pitfall in 18F-FDG-PET/CT. Clin Nucl Med 40(11):e518–e519.  https://doi.org/10.1097/RLU.0000000000000887 CrossRefPubMedGoogle Scholar
  45. 45.
    Mellati M, Eaton KD, Brooks-Worrell BM, Hagopian WA, Martins R, Palmer JP, Hirsch IB (2015) Anti-PD-1 and Anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care 38:e137–e138.  https://doi.org/10.2337/dc15-0889 CrossRefPubMedGoogle Scholar
  46. 46.
    Gaudy C, Clévy C, Monestier S, Dubois N, Préau Y, Mallet S, Richard MA, Grob JJ, Valéro R, Béliard S (2015) Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care 38:e182–e183.  https://doi.org/10.2337/dc15-1331 CrossRefPubMedGoogle Scholar
  47. 47.
    Cochain C, Chaudhari SM, Koch M, Wiendl H, Eckstein HH, Zernecke A (2014) Programmed cell death-1 deficiency exacerbates T cell activation and atherogenesis despite expansion of regulatory T cells in atherosclerosis-prone mice. PLoS One 9:93280CrossRefGoogle Scholar
  48. 48.
    Bu DX, Tarrio M, Maganto-Garcia E, Stavrakis G, Tajima G, Lederer J, Jarolim P, Freeman GJ, Sharpe AH, Lichtman AH (2011) Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol 31:1100–1107CrossRefGoogle Scholar
  49. 49.
    Inoue H, Park JH, Kiyotani K, Zewde M, Miyashita A, Jinnin M, Kiniwa Y, Okuyama R, Tanaka R, Fujisawa Y et al (2016) Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma. Oncoimmunology 5:1204–1507CrossRefGoogle Scholar
  50. 50.
    Shahabi V, Berman D, Chasalow SD, Wang L, Tsuchihashi Z, Hu B, Panting L, Jure-Kunkel M, Ji RR (2013) Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune- related gastrointestinal adverse events. J Transl Med 11:75CrossRefGoogle Scholar
  51. 51.
    Albarel F, Gaudy C, Castinetti F, Carré T, Morange I, Conte-Devolx B, Grob JJ, Brue T (2015) Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur J Endocrinol 172:195–204CrossRefGoogle Scholar
  52. 52.
    Higham CE, Olsson-Brown A, Carroll P, Cooksley T, Larkin J, Lorigan P, Morganstein D, Trainer PJ, Society for Endocrinology Clinical Committee (2018) Society for Endocrinology Endocrine Emergency Guidance: acute management of the endocrine complications of checkpoint inhibitor therapy. Endocr Connect 7:G1–G7.  https://doi.org/10.1530/ec-18-0068 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Min L, Hodi FS, Giobbie-Hurder A, Ott PA, Luke JJ, Donahue H, Davis M, Carroll RS, Kaiser UB (2015) Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. Clin Cancer Res 21:749–755CrossRefGoogle Scholar
  54. 54.
    Kumar V, Chaundary N, Garg M, Floudas CS, Soni P, Chandra AB (2017) Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 8:311.  https://doi.org/10.3389/fphar.2017.00311 CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Haanen JBAG, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, Jordan K, Guidelines Committee ESMO (2017) Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 28:iv119–iv142.  https://doi.org/10.1093/annonc/mdx225 CrossRefPubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2018

Authors and Affiliations

  • R. M. Ruggeri
    • 1
  • A. Campennì
    • 2
  • G. Giuffrida
    • 1
    Email author
  • P. Trimboli
    • 3
  • L. Giovanella
    • 3
  • F. Trimarchi
    • 4
  • S. Cannavò
    • 5
  1. 1.Unit of Endocrinology, Department of Clinical and Experimental MedicineBuilding H, Floor 4, “G. Martino” University Hospital, University of MessinaMessinaItaly
  2. 2.Unit of Nuclear Medicine, Department of Biomedical and Dental Sciences and Morpho-Functional ImagingUniversity of MessinaMessinaItaly
  3. 3.Nuclear Medicine, PET/CT CentreOncology Institute of Southern SwitzerlandBellinzonaSwitzerland
  4. 4.Accademia Peloritana dei Pericolanti at the University of MessinaMessinaItaly
  5. 5.Department of Human Pathology of Adulthood and Childhood “Gaetano Barresi”University of MessinaMessinaItaly

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