Skip to main content

Advertisement

SpringerLink
Log in

A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Immune checkpoint inhibitors such as pembrolizumab, ipilimumab, and nivolumab, now FDA-approved for use in treating several types of cancer, have been associated with immune-related adverse effects. Specifically, the antibodies targeting the programmed-cell death-1 immune checkpoint, pembrolizumab and nivolumab, have been rarely reported to induce the development of type 1 diabetes mellitus. Here we describe a case of a patient who developed antibody-positive type 1 diabetes mellitus following treatment with pembrolizumab in combination with systemic chemotherapy for metastatic adenocarcinoma of the lung. We will also provide a brief literature review of other rarely reported cases of type 1 diabetes presenting after treatment with pembrolizumab and nivolumab, as well as discussion regarding potential mechanisms of this adverse effect and its importance as these drugs continue to become even more widespread.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ALK:

Anaplastic lymphoma kinase

CK:

Cytokeratin

CT:

Computed tomography

DKA:

Diabetic ketoacidosis

EGFR:

Epidermal growth factor receptor

GAD:

Glutamic acid decarboxylase

HbA1c:

Hemoglobin A1c

IA:

Islet antigen

ICA:

Islet cell autoantigen

KRAS:

Kirsten rat sarcoma

NOD:

Non-obese diabetic

NR:

Not reported

NSCLC:

Non-small cell lung cancer

PAX:

Paired box gene

RCC:

Renal cell carcinoma

SCLC:

Small cell lung cancer

T1DM:

Type 1 diabetes mellitus

Treg:

Regulatory T cell

TTF:

Thyroid transcription factor

UD:

Undetectable

References

  1. Yamazaki N, Kiyohara Y, Uhara H, Fukushima S, Uchi H, Shibagaki N, Tsutsumida A, Yoshikawa S, Okuyama R, Ito Y, Tokudome T (2015) Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma. Cancer Chemother Pharmacol 76(5):997–1004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Min L, Ibrahim N (2013) Ipilimumab-induced autoimmune adrenalitis. Lancet Diabetes Endocrinol 1(3):e15

    Article  PubMed  PubMed Central  Google Scholar 

  3. Min L, Vaidya A, Becker C (2011) Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol 164(2):303–307

    Article  CAS  PubMed  Google Scholar 

  4. Keytruda (pembrolizumab) (2014) [package insert] Merck & Co., Inc., Whitehouse Station, NJ

  5. Opdivo (nivolumab) (2014) [package insert] Bristol-Myers Squibb Company, Princeton, NJ

  6. Sansom DM (2000) CD28, CTLA-4 and their ligands: who does what and to whom? Immunology 101(2):169–177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. He J, Hu Y, Hu M, Li B (2015) Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep 5:13110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hughes J, Vudattu N, Sznol M, Gettinger S, Kluger H, Lupsa B, Herold KC (2015) Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 38(4):e55–e57

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Gaudy C, Clevy C, Monestier S, Dubois N, Preau Y, Mallet S, Richard MA, Grob JJ, Valero R, Beliard S (2015) Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care 38(11):e182–e183

    Article  PubMed  Google Scholar 

  10. Martin-Liberal J, Furness AJ, Joshi K, Peggs KS, Quezada SA, Larkin J (2015) Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother 64(6):765–767

    Article  PubMed  Google Scholar 

  11. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, Gutzmer R, Utikal JS, Goppner D, Hassel JC, Meier F, Tietze JK, Thomas I, Weishaupt C, Leverkus M, Wahl R, Dietrich U, Garbe C, Kirchberger MC, Eigentler T, Berking C, Gesierich A, Krackhardt AM, Schadendorf D, Schuler G, Dummer R, Heinzerling LM (2016) Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 60:190–209

    Article  CAS  PubMed  Google Scholar 

  12. Hansen E, Sahasrabudhe D, Sievert L (2016) A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome. Cancer Immunol Immunother 65(6):765–767

    Article  PubMed  Google Scholar 

  13. Teramoto Y, Nakamura Y, Asami Y, Imamura T, Takahira S, Nemoto M, Sakai G, Shimada A, Noda M, Yamamoto A (2016) Case of type 1 diabetes associated with less-dose nivolumab therapy in a melanoma patient. J Dermatol. doi:10.1111/1346-8138.13486

    Google Scholar 

  14. Miyoshi Y, Ogawa O, Oyama Y (2016) Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant type 1 diabetes. Tohoku J Exp Med 239(2):155–158

    Article  PubMed  Google Scholar 

  15. Okamoto M, Okamoto M, Gotoh K, Masaki T, Ozeki Y, Ando H, Anai M, Sato A, Yoshida Y, Ueda S, Kakuma T, Shibata H (2016) Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy. J Diabetes Investig. doi:10.1111/jdi.12531

    PubMed  PubMed Central  Google Scholar 

  16. Chianese-Bullock KA, Woodson EM, Tao H, Boerner SA, Smolkin M, Grosh WW, Neese PY, Merrill P, Petroni GR, Slingluff CL Jr (2005) Autoimmune toxicities associated with the administration of antitumor vaccines and low-dose interleukin-2. J Immunother 28(4):412–419

    Article  CAS  PubMed  Google Scholar 

  17. Soni N, Meropol NJ, Porter M, Caligiuri MA (1996) Diabetes mellitus induced by low-dose interleukin-2. Cancer Immunol Immunother 43(1):59–62

    Article  CAS  PubMed  Google Scholar 

  18. Shiba T, Morino Y, Tagawa K, Fujino H, Unuma T (1995) Onset of diabetes with high titer anti-GAD antibody after IFN therapy for chronic hepatitis. Diabetes Res Clin Pract 30(3):237–241

    Article  CAS  PubMed  Google Scholar 

  19. Kawazoe T, Araki M, Lin Y, Ogawa M, Okamoto T, Yamamura T, Wakakura M, Murata M (2012) New-onset type 1 diabetes mellitus and anti-aquaporin-4 antibody positive optic neuritis associated with type 1 interferon therapy for chronic hepatitis C. Intern Med 51(18):2625–2629

    Article  CAS  PubMed  Google Scholar 

  20. Yamazaki M, Sato A, Takeda T, Komatsu M (2010) Distinct clinical courses in type 1 diabetes mellitus induced by peg-interferon-alpha treatment for chronic hepatitis C. Intern Med 49(5):403–407

    Article  CAS  PubMed  Google Scholar 

  21. Lv YY, Shi BY, Guo H (2008) Abrupt onset of type 1 diabetes mellitus during recombinant interferon-alpha 2b therapy in a patient with chronic hepatitis B. World J Gastroenterol 14(29):4713–4715

    Article  PubMed  PubMed Central  Google Scholar 

  22. Recasens M, Aguilera E, Ampurdanes S, Sanchez Tapias JM, Simo O, Casamitjana R, Conget I (2001) Abrupt onset of diabetes during interferon-alpha therapy in patients with chronic hepatitis C. Diabet Med 18(9):764–767

    Article  CAS  PubMed  Google Scholar 

  23. Fabris P, Betterle C, Greggio NA, Zanchetta R, Bosi E, Biasin MR, de Lalla F (1998) Insulin-dependent diabetes mellitus during alpha-interferon therapy for chronic viral hepatitis. J Hepatol 28(3):514–517

    Article  CAS  PubMed  Google Scholar 

  24. Li Q, McDevitt HO (2011) The role of interferon alpha in initiation of type I diabetes in the NOD mouse. Clin Immunol 140(1):3–7

    Article  CAS  PubMed  Google Scholar 

  25. Li Q, Xu B, Michie SA, Rubins KH, Schreriber RD, McDevitt HO (2008) Interferon-alpha initiates type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci USA 105(34):12439–12444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H Jr, Sayegh MH (2003) The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 198(1):63–69

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kochupurakkal NM, Kruger AJ, Tripathi S, Zhu B, Adams LT, Rainbow DB, Rossini A, Greiner DL, Sayegh MH, Wicker LS, Guleria I (2014) Blockade of the programmed death-1 (PD1) pathway undermines potent genetic protection from type 1 diabetes. PLoS One 9(2):e89561

    Article  PubMed  PubMed Central  Google Scholar 

  28. Guleria I, Bupp MG, Dada S, Fife B, Tang Q, Ansari MJ, Trikudanathan S, Vadivel N, Fiorina P, Yagita H, Azuma M, Atkinson M, Bluestone JA, Sayegh MH (2007) Mechanisms of PDL1-mediated regulation of autoimmune diabetes. Clin Immunol 125(1):16–25

    Article  CAS  PubMed  Google Scholar 

  29. Perri V, Russo B, Crino A, Schiaffini R, Giorda E, Cappa M, Rosado MM, Fierabracci A (2015) Expression of PD-1 molecule on regulatory T lymphocytes in patients with insulin-dependent diabetes mellitus. Int J Mol Sci 16(9):22584–22605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fujisawa R, Haseda F, Tsutsumi C, Hiromine Y, Noso S, Kawabata Y, Mitsui S, Terasaki J, Ikegami H, Imagawa A, Hanafusa T (2015) Low programmed cell death-1 (PD-1) expression in peripheral CD4(+) T cells in Japanese patients with autoimmune type 1 diabetes. Clin Exp Immunol 180(3):452–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pociot F, Lernmark A (2016) Genetic risk factors for type 1 diabetes. Lancet 387(10035):2331–2339

    Article  CAS  PubMed  Google Scholar 

  32. Noble JA, Valdes AM (2011) Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diabetes Rep 11(6):533–542

    Article  CAS  Google Scholar 

  33. Spain L, Larkin J, Martin-Liberal J (2016) Determining predictive factors for immune checkpoint inhibitor toxicity: Response to Letter to the Editors “A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome”. Cancer Immunol Immunother 65(6):769–770

    Article  PubMed  Google Scholar 

  34. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25(21):9543–9553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. International Expert, C. (2009) International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32(7):1327–1334

    Article  Google Scholar 

Download references

Author information

Author notes

    Authors and Affiliations

    1. Developmental Therapeutics Program of the Division of Hematology/Oncology, Northwestern University, Chicago, IL, 60611, USA

      Young Kwang Chae, Nisha Mohindra & Francis Giles

    2. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, 60611, USA

      Young Kwang Chae, Nisha Mohindra, Jyoti Patel & Francis Giles

    3. Feinberg School of Medicine, Northwestern University, 645 N. Michigan Ave, Suite 1006, Chicago, IL, 60611, USA

      Young Kwang Chae, Lauren Chiec, Nisha Mohindra, Jyoti Patel & Francis Giles

    4. University of Virginia School of Medicine, Charlottesville, VA, 22908-0395, USA

      Ryan Gentzler

    5. The University of Chicago Medicine, Chicago, IL, 60637, USA

      Jyoti Patel

    Authors
    1. Young Kwang Chae
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Lauren Chiec
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Nisha Mohindra
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Ryan Gentzler
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jyoti Patel
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Francis Giles
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Young Kwang Chae.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Young Kwang Chae and Lauren Chiec have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Chae, Y.K., Chiec, L., Mohindra, N. et al. A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Cancer Immunol Immunother 66, 25–32 (2017). https://doi.org/10.1007/s00262-016-1913-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00262-016-1913-7

    Keywords

    Search

    Navigation