Abstract
Programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) inhibitors have been highlighted in the field of cancer treatment. The interaction between PD-1 and PD-L1 is thought to play an important role in the regulation of the self-immune tolerance mechanism, so blocking these molecules may cause serious immune-related adverse events (IrAE), including fulminant insulin-dependent (type 1) diabetes. Here, we describe a patient with fulminant type 1 diabetes induced by nivolumab, an anti-PD-1 antibody. The patient, a 78-year-old man, was being treated with nivolumab as a third-line treatment for squamous cell carcinoma of the lung. After three cycles, he experienced an abrupt flare-up of the blood glucose within half a day. His blood glucose further increased without clinical symptoms until his hospital visit. Laboratory data showed the complete exhaustion of intrinsic insulin and the elevation of serum antibody titer to glutamic acid decarboxylase (GAD). Although the patient was previously diagnosed with non-insulin-dependent (type 2) diabetes, his disease activity had been well controlled with oral medication and low-dose insulin therapy until just before the flare-up. Because of the laboratory findings and the extremely rapid onset of hyperglycemia, a diagnosis of fulminant, rather than the rapid onset, type 1 diabetes related to nivolumab therapy was strongly suspected. Our case study indicates that fulminant hyperglycemia can occur extremely rapidly. The blood glucose of patients receiving PD-1 antibody therapy should be closely monitored.
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Abbreviations
- AUC:
-
Area under the curve
- CT:
-
Computed tomography
- CTLA-4:
-
Cytotoxic T-lymphocyte-associated protein-4
- DM:
-
Diabetes mellitus
- EIA:
-
Enzyme immunoassay
- GAD:
-
Glutamic acid decarboxylase
- HbA1c:
-
Hemoglobin A1c
- HLA:
-
Human leukocyte antigen
- IrAE:
-
Immune-related adverse event
- MRI:
-
Magnetic resonance imaging
- NSCLC:
-
Non-small cell lung cancer
- SPIDDM:
-
Slowly progressive insulin-dependent diabetes mellitus
References
De Velasco G, Je Y, Bosse D et al (2017) Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res 5:312–318. https://doi.org/10.1158/2326-6066.CIR-16-0237
Michot JM, Bigenwald C, Champiat S et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148. https://doi.org/10.1016/j.ejca.2015.11.016
Brahmer J, Reckamp KL, Baas P et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123–135. https://doi.org/10.1056/NEJMoa1504627
Robert C, Long GV, Brady B et al (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330. https://doi.org/10.1056/NEJMoa1412082
Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813. https://doi.org/10.1056/NEJMoa1510665
Ferris RL, Blumenschein G Jr, Fayette J et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 375:1856–1867. https://doi.org/10.1056/NEJMoa1602252
Younes A, Santoro A, Shipp M et al (2016) Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283–1294. https://doi.org/10.1016/s1470-2045(16)30167-x
Le DT, Uram JN, Wang H et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520. https://doi.org/10.1056/NEJMoa1500596
Kudo T, Hamamoto Y, Kato K et al (2017) Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 18:631–639. https://doi.org/10.1016/s1470-2045(17)30181-x
Costa RCB, Agulnik M, Rademaker AW et al (2017) Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. Oncotarget 8:8910–8920
Hickmott L, De La Pena H, Turner H et al (2017) Anti -PD-L1 atezolizumab-induced autoimmune diabetes: a case report and review of the literature. Target. Oncol. 12:235–241. https://doi.org/10.1007/s11523-017-0480-y
Martin-Liberal J, Furness AJ, Joshi K et al (2015) Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother 64:765–767. https://doi.org/10.1007/s00262-015-1689-1
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 65:765–767. https://doi.org/10.1007/s00262-016-1835-4
Kong SH, Lee SY, Yang YS, Kim TM, Kwak SH (2016) Anti-programmed cell death 1 therapy triggering diabetic ketoacidosis and fulminant type 1 diabetes. Acta Diabetol 53:853–856. https://doi.org/10.1007/s00592-016-0872-y
Munakata W, Ohashi K, Yamauchi N, Tobinai K (2017) Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma. Int J Hematol 105:383–386. https://doi.org/10.1007/s12185-016-2101-4
Miyoshi Y, Ogawa O, Oyama Y (2016) Nivolumab, an anti-programmed cell death-1 antibody, induces fulminant Type 1 Diabetes. Tohoku J Exp Med 239:155–158
Imagawa A, Hnafusa T. Miyagawa J, Matsyzawa Y (2000) A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence od diabetes-related antibodies. N Engl J Med 342:301–307
Imagawa A, Hanafusa T (2011) Fulminant type 1 diabetes–an important subtype in East Asia. Diabetes Metab Res Rev 27:959–964. https://doi.org/10.1002/dmrr.1236
Iwaoka T (2003) A case of fulminant type 1 diabetes with transiently positive anti-GAD antibodies. Endocrine J 50:225–231
Kahara T, Takamura T, Ando H et al (2003) Fulminating onset type 1 diabetes with positivity for anti-GAD antibody and elevated pancreatic exocrine enzyme concentrations. Intern Med 42:517–520
Makino SH, Iwata S, Fujiwara M,M (2009) A case of abrupt onset autoimmune type 1 diabetes mimicking fulminant type 1 diabetes. Endocrine J 56:1113–1117
Lowe JR, Perry DJ, Salama AKS et al (2016) Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy. J Immunother Cancer 4:89. https://doi.org/10.1186/s40425-016-0196-z
Kobayashi T, Tanemoto T, Nakanishi K et al (1993) Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care 16:780–788
Osorio JC, Ni A, Chaft JE et al (2017) Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol 28:583–589. https://doi.org/10.1093/annonc/mdw640
Thibult ML, Mamessier E, Gertner-Dardenne J et al (2013) PD-1 is a novel regulator of human B-cell activation. Int Immunol 25:129–137. https://doi.org/10.1093/intimm/dxs098
Hughes J, Vudattu N, Sznol M et al (2015) Precipitation of autoimmune diabetes with anti PD-1 immunotherapy. Diabetes care 38:e55–e57. https://doi.org/10.2337/dc14-2349
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
Hofmann L, Forschner A, Loquai C et al (2016) Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 60:190–209. https://doi.org/10.1016/j.ejca.2016.02.025
Chae YK, Chiec L, Mohindra N et al (2017) 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. https://doi.org/10.1007/s00262-016-1913-7
Kapke J, Shaheen Z, Kilari D et al (2017) Immune checkpoint inhibitor associated type 1 diabetes mellitus: case series, review of literature and optimal management. Case Rep Oncol 10:897–909. https://doi.org/10.1159/000480634
Godwin JL, Jaggi S, Sharda I et al (2017) Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. J Immunother Cancer 5:40–46. https://doi.org/10.1186/s40425-017-0245-2
Gauci ML, Laly P, Vidal-Trecan T et al (2017) Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. Cancer Immunol Immunother 66:1399–1410. https://doi.org/10.1007/s00262-017-2033-8
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All the authors had full access to all the data in the study. Manuscript was prepared by NM and GK. Clinical data were prepared and interpreted by NM, GK, CK, SM, and Y T. HH, KK, and ME reviewed the paper and provided important advice.
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This report was approved by ethics committee of Yao-Tokushukai General Hospital. Written informed consent was obtained from the patient for this report.
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Matsuura, N., Koh, G., Konishi, C. et al. Fulminant onset of insulin-dependent diabetes with positive anti-GAD antibody titers during treatment with nivolumab in a patient with NSCLC. Cancer Immunol Immunother 67, 1417–1424 (2018). https://doi.org/10.1007/s00262-018-2203-3
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DOI: https://doi.org/10.1007/s00262-018-2203-3