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Erschienen in: Cancer Immunology, Immunotherapy 1/2017

19.10.2016 | Original Article

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

verfasst von: Young Kwang Chae, Lauren Chiec, Nisha Mohindra, Ryan Gentzler, Jyoti Patel, Francis Giles

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 1/2017

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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.
Literatur
1.
Zurück zum Zitat 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):997–1004CrossRefPubMedPubMedCentral 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):997–1004CrossRefPubMedPubMedCentral
3.
Zurück zum Zitat Min L, Vaidya A, Becker C (2011) Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol 164(2):303–307CrossRefPubMed Min L, Vaidya A, Becker C (2011) Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol 164(2):303–307CrossRefPubMed
4.
Zurück zum Zitat Keytruda (pembrolizumab) (2014) [package insert] Merck & Co., Inc., Whitehouse Station, NJ Keytruda (pembrolizumab) (2014) [package insert] Merck & Co., Inc., Whitehouse Station, NJ
5.
Zurück zum Zitat Opdivo (nivolumab) (2014) [package insert] Bristol-Myers Squibb Company, Princeton, NJ Opdivo (nivolumab) (2014) [package insert] Bristol-Myers Squibb Company, Princeton, NJ
7.
Zurück zum Zitat 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 5:13110CrossRefPubMedPubMedCentral 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 5:13110CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat 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–e57PubMedPubMedCentral 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–e57PubMedPubMedCentral
9.
Zurück zum Zitat 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–e183CrossRefPubMed 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–e183CrossRefPubMed
10.
Zurück zum Zitat 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):765–767CrossRefPubMed 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):765–767CrossRefPubMed
11.
Zurück zum Zitat 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 60:190–209CrossRefPubMed 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 60:190–209CrossRefPubMed
12.
Zurück zum Zitat 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):765–767CrossRefPubMed 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):765–767CrossRefPubMed
13.
Zurück zum Zitat 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 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
14.
Zurück zum Zitat 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):155–158CrossRefPubMed 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):155–158CrossRefPubMed
15.
Zurück zum Zitat 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 PubMedPubMedCentral 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 PubMedPubMedCentral
16.
Zurück zum Zitat 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):412–419CrossRefPubMed 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):412–419CrossRefPubMed
17.
Zurück zum Zitat Soni N, Meropol NJ, Porter M, Caligiuri MA (1996) Diabetes mellitus induced by low-dose interleukin-2. Cancer Immunol Immunother 43(1):59–62CrossRefPubMed Soni N, Meropol NJ, Porter M, Caligiuri MA (1996) Diabetes mellitus induced by low-dose interleukin-2. Cancer Immunol Immunother 43(1):59–62CrossRefPubMed
18.
Zurück zum Zitat 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):237–241CrossRefPubMed 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):237–241CrossRefPubMed
19.
Zurück zum Zitat 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):2625–2629CrossRefPubMed 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):2625–2629CrossRefPubMed
20.
Zurück zum Zitat 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):403–407CrossRefPubMed 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):403–407CrossRefPubMed
21.
Zurück zum Zitat 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):4713–4715CrossRefPubMedPubMedCentral 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):4713–4715CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat 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):764–767CrossRefPubMed 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):764–767CrossRefPubMed
23.
Zurück zum Zitat 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):514–517CrossRefPubMed 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):514–517CrossRefPubMed
24.
Zurück zum Zitat Li Q, McDevitt HO (2011) The role of interferon alpha in initiation of type I diabetes in the NOD mouse. Clin Immunol 140(1):3–7CrossRefPubMed Li Q, McDevitt HO (2011) The role of interferon alpha in initiation of type I diabetes in the NOD mouse. Clin Immunol 140(1):3–7CrossRefPubMed
25.
Zurück zum Zitat 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):12439–12444CrossRefPubMedPubMedCentral 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):12439–12444CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat 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):63–69CrossRefPubMedPubMedCentral 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):63–69CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat 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):e89561CrossRefPubMedPubMedCentral 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):e89561CrossRefPubMedPubMedCentral
28.
Zurück zum Zitat 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):16–25CrossRefPubMed 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):16–25CrossRefPubMed
29.
Zurück zum Zitat 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):22584–22605CrossRefPubMedPubMedCentral 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):22584–22605CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat 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):452–457CrossRefPubMedPubMedCentral 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):452–457CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat Pociot F, Lernmark A (2016) Genetic risk factors for type 1 diabetes. Lancet 387(10035):2331–2339CrossRefPubMed Pociot F, Lernmark A (2016) Genetic risk factors for type 1 diabetes. Lancet 387(10035):2331–2339CrossRefPubMed
32.
Zurück zum Zitat Noble JA, Valdes AM (2011) Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diabetes Rep 11(6):533–542CrossRef Noble JA, Valdes AM (2011) Genetics of the HLA region in the prediction of type 1 diabetes. Curr Diabetes Rep 11(6):533–542CrossRef
33.
Zurück zum Zitat 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):769–770CrossRefPubMed 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):769–770CrossRefPubMed
34.
Zurück zum Zitat 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):9543–9553CrossRefPubMedPubMedCentral 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):9543–9553CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat International Expert, C. (2009) International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32(7):1327–1334CrossRef International Expert, C. (2009) International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32(7):1327–1334CrossRef
Metadaten
Titel
A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes
verfasst von
Young Kwang Chae
Lauren Chiec
Nisha Mohindra
Ryan Gentzler
Jyoti Patel
Francis Giles
Publikationsdatum
19.10.2016
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 1/2017
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-016-1913-7

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