Key Points
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The emergence of cancer immunotherapy has revolutionized cancer treatment but is associated with serious immune-related adverse effects (IRAEs)
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Cytotoxic T-lymphocyte antigen 4 (CTLA4)-targeted immunotherapy is associated with increased susceptibility to hypophysitis and primary thyroid dysfunction
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Programmed cell death protein 1 (PD1)-targeted immunotherapy is associated with primary thyroid dysfunction and type 1 diabetes mellitus
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CTLA4–PD1 combination therapy has an elevated incidence of hypothyroidism and possibly incidence rates of hypophysitis similar to those with monotherapy with CTLA4 antibodies
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IRAEs might be associated with improved clinical response of tumours to immunotherapy, but further studies are needed to evaluate this possible effect
Abstract
Advances in cancer therapy in the past few years include the development of medications that modulate immune checkpoint proteins. Cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are two co-inhibitory receptors that are expressed on activated T cells against which therapeutic blocking antibodies have reached routine clinical use. Immune checkpoint blockade can induce inflammatory adverse effects, termed immune-related adverse events (IRAEs), which resemble autoimmune disease. In this Review, we describe the current data regarding immune-related endocrinopathies, including hypophysitis, thyroid dysfunction and diabetes mellitus. We discuss the clinical management of these endocrinopathies within the context of our current understanding of the mechanisms of IRAEs.
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Change history
06 February 2017
In the CTLA4 antibodies section of the above article published online 20 January 2017, 'finding' was misspelled. This has been corrected online.
References
Pandolfi, F. et al. Strategies to overcome obstacles to successful immunotherapy of melanoma. Int. J. Immunopathol. Pharmacol. 21, 493–500 (2008).
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).
Stewart, T. J. & Smyth, M. J. Improving cancer immunotherapy by targeting tumor-induced immune suppression. Cancer Metastasis Rev. 30, 125–140 (2011).
Linsley, P. S. et al. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J. Exp. Med. 173, 721–730 (1991).
Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA 107, 4275–4280 (2010).
Peggs, K. S., Quezada, S. A., Korman, A. J. & Allison, J. P. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr. Opin. Immunol. 18, 206–213 (2006).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Fathman, C. G. & Lineberry, N. B. Molecular mechanisms of CD4+ T-cell anergy. Nat. Rev. Immunol. 7, 599–609 (2007).
Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295–307 (2006).
Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).
Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).
Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).
Topalian, S. L., Drake, C. G. & Pardoll, D. M. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 24, 207–212 (2012).
Agata, Y. et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int. Immunol. 8, 765–772 (1996).
Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).
Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).
Yamazaki, T. et al. Expression of programmed death 1 ligands by murine T cells and APC. J. Immunol. 169, 5538–5545 (2002).
Okazaki, T. & Honjo, T. PD-1 and PD-1 ligands: from discovery to clinical application. Int. Immunol. 19, 813–824 (2007).
Zou, W. & Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat. Rev. Immunol. 8, 467–477 (2008).
Taube, J. M. et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci. Transl Med. 4, 127ra37 (2012).
Chow, L. Q. Exploring novel immune-related toxicities and endpoints with immune-checkpoint inhibitors in non-small cell lung cancer. Am. Soc. Clin. Oncol. Educ. Book http://dx.doi.org/10.1200/EdBook_AM.2013.33.e280 (2013).
Peggs, K. S., Quezada, S. A. & Allison, J. P. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol. Rev. 224, 141–165 (2008).
Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).
Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
Postow, M. A. Managing immune checkpoint-blocking antibody side effects. Am. Soc. Clin. Oncol. Educ. Book http://dx.doi.org/10.14694/EdBook_AM.2015.35.76 (2015).
Fong, L. & Small, E. J. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J. Clin. Oncol. 26, 5275–5283 (2008).
Torino, F. et al. Endocrine side-effects of anti-cancer drugs: mAbs and pituitary dysfunction: clinical evidence and pathogenic hypotheses. Eur. J. Endocrinol. 169, R153–R164 (2013).
Torino, F., Barnabei, A., De Vecchis, L., Salvatori, R. & Corsello, S. M. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist 17, 525–535 (2012).
Corsello, S. M. et al. Endocrine side effects induced by immune checkpoint inhibitors. J. Clin. Endocrinol. Metab. 98, 1361–1375 (2013).
Ryder, M., Callahan, M., Postow, M. A., Wolchok, J. & Fagin, J. A. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr. Relat. Cancer 21, 371–381 (2014).
Iwama, S. et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci. Transl Med. 6, 230ra45 (2014).
Sharma, P., Wagner, K., Wolchok, J. D. & Allison, J. P. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat. Rev. Cancer 11, 805–812 (2011).
Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).
Faje, A. T. et al. Ipilimumab-induced hypophysitis: a detailed longitudinal analysis in a large cohort of patients with metastatic melanoma. J. Clin. Endocrinol. Metab. 99, 4078–4085 (2014).
Eatrides, J. et al. in AACR Advances in Melanoma: from Biology to Therapy (American Association for Cancer Research, 2014).
Weber, J. S., Kahler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).
Yang, J. C. et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. 30, 825–830 (2007).
Hamnvik, O. P., Larsen, P. R. & Marqusee, E. Thyroid dysfunction from antineoplastic agents. J. Natl Cancer Inst. 103, 1572–1587 (2011).
Reichert, J. M. Marketed therapeutic antibodies compendium. MAbs 4, 413–415 (2012).
Ribas, A. et al. Phase III, open-label, randomized, comparative study of tremelimumab (CP-675,206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC]) in patients with advanced melanoma [abstract]. J. Clin. Oncol. 26, LBA9011 (2008).
Ribas, A. et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 31, 616–622 (2013).
Chung, K. Y. et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J. Clin. Oncol. 28, 3485–3490 (2010).
Voskens, C. J. et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS ONE 8, e53745 (2013).
Caturegli, P. et al. Autoimmune hypophysitis. Endocr. Rev. 26, 599–614 (2005).
Chodakiewitz, Y., Brown, S., Boxerman, J. L., Brody, J. M. & Rogg, J. M. Ipilimumab treatment associated pituitary hypophysitis: clinical presentation and imaging diagnosis. Clin. Neurol. Neurosurg. 125, 125–130 (2014).
Albarel, F. et al. Long-term follow-up of ipilimumab-induced hypophysitis, a common adverse event of the anti-CTLA-4 antibody in melanoma. Eur. J. Endocrinol. 172, 195–204 (2015).
Min, L. et al. Systemic high-dose corticosteroid treatment does not improve the outcome of ipilimumab-related hypophysitis: a retrospective cohort study. Clin. Cancer Res. 21, 749–755 (2015).
Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).
Landek-Salgado, M. A., Leporati, P., Lupi, I., Geis, A. & Caturegli, P. Growth hormone and proopiomelanocortin are targeted by autoantibodies in a patient with biopsy-proven IgG4-related hypophysitis. Pituitary 15, 412–419 (2012).
Faje, A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 19, 82–92 (2016).
Boasberg, P., Hamid, O. & O'Day, S. Ipilimumab: unleashing the power of the immune system through CTLA-4 blockade. Semin. Oncol. 37, 440–449 (2010).
Kaehler, K. C. et al. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin. Oncol. 37, 485–498 (2010).
Juszczak, A., Gupta, A., Karavitaki, N., Middleton, M. R. & Grossman, A. B. Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review. Eur. J. Endocrinol. 167, 1–5 (2012).
Dillard, T., Yedinak, C. G., Alumkal, J. & Fleseriu, M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 13, 29–38 (2010).
Min, L., Vaidya, A. & Becker, C. Association of ipilimumab therapy for advanced melanoma with secondary adrenal insufficiency: a case series. Endocr. Pract. 18, 351–355 (2012).
Falorni, A., Minarelli, V., Bartoloni, E., Alunno, A. & Gerli, R. Diagnosis and classification of autoimmune hypophysitis. Autoimmun. Rev. 13, 412–416 (2014).
Blansfield, J. A. et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J. Immunother. 28, 593–598 (2005).
Weber, J. S. et al. 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, 1675–1682 (2013).
Glezer, A. & Bronstein, M. D. Pituitary autoimmune disease: nuances in clinical presentation. Endocrine 42, 74–79 (2012).
Maker, A. V. et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J. Immunother. 29, 455–463 (2006).
Carpenter, K. J., Murtagh, R. D., Lilienfeld, H., Weber, J. & Murtagh, F. R. Ipilimumab-induced hypophysitis: MR imaging findings. AJNR Am. J. Neuroradiol. 30, 1751–1753 (2009).
Phan, G. Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100, 8372–8377 (2003).
Quirk, S. K., Shure, A. K. & Agrawal, D. K. Immune-mediated adverse events of anticytotoxic T lymphocyte-associated antigen 4 antibody therapy in metastatic melanoma. Transl Res. 166, 412–424 (2015).
Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014).
Gettinger, S. N. et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 33, 2004–2012 (2015).
Ribas, A. et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J. Clin. Oncol. 23, 8968–8977 (2005).
Camacho, L. H. et al. Phase I/II trial of tremelimumab in patients with metastatic melanoma. J. Clin. Oncol. 27, 1075–1081 (2009).
Ralph, C. et al. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin. Cancer Res. 16, 1662–1672 (2010).
Kirkwood, J. M. et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin. Cancer Res. 16, 1042–1048 (2010).
Mitchell, A. L. et al. Programmed death ligand 1 (PD-L1) gene variants contribute to autoimmune Addison's disease and Graves' disease susceptibility. J. Clin. Endocrinol. Metab. 94, 5139–5145 (2009).
Kristof, R. A., Van Roost, D., Klingmuller, D., Springer, W. & Schramm, J. Lymphocytic hypophysitis: non-invasive diagnosis and treatment by high dose methylprednisolone pulse therapy? J. Neurol. Neurosurg. Psychiatry 67, 398–402 (1999).
Chico, A. et al. Reversible endocrine dysfunction and pituitary stalk enlargement. J. Endocrinol. Invest. 21, 122–127 (1998).
Hinrichs, C. S., Palmer, D. C., Rosenberg, S. A. & Restifo, N. P. Glucocorticoids do not inhibit antitumor activity of activated CD8+ T cells. J. Immunother. 28, 517–524 (2005).
Harmankaya, K. et al. Continuous systemic corticosteroids do not affect the ongoing regression of metastatic melanoma for more than two years following ipilimumab therapy. Med. Oncol. 28, 1140–1144 (2011).
Amin, A. et al. Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity. J. Clin. Oncol. 27, 9037 (2009).
Grob, J. J., Hamid, O. & Wolchok, J. in Proceedings of the Joint ECCO 15-34th ESMO Multidisciplinary Congress (European Society for Medical Oncology, 2009).
Di Giacomo, A. M., Biagioli, M. & Maio, M. The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications. Semin. Oncol. 37, 499–507 (2010).
[No authors listed.] YERVOY (ipilimumab): serious and fatal immune-mediated adverse reactions. Ipilimumab US prescribing information: risk evaluation and mitigation strategy (REMS). Yervoy http://www.yervoy.com/ (2012).
Oelkers, W. Hyponatremia and inappropriate secretion of vasopressin (antidiuretic hormone) in patients with hypopituitarism. N. Engl. J. Med. 321, 492–496 (1989).
Attia, P. et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol. 23, 6043–6053 (2005).
Miller, K. K. et al. Androgen deficiency in women with hypopituitarism. J. Clin. Endocrinol. Metab. 86, 561–567 (2001).
Kaplan, M. M. et al. Prevalence of abnormal thyroid function test results in patients with acute medical illnesses. Am. J. Med. 72, 9–16 (1982).
Agabegi, S. S. & Derby, E. A. (eds) Step-up to Medicine 3rd edn (Lippincott Williams & Wilkins, 2013).
Downey, S. G. et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin. Cancer Res. 13, 6681–6688 (2007).
Ku, G. Y. et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116, 1767–1775 (2010).
Eggermont, A. M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 16, 522–530 (2015).
Small, E. J. et al. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 13, 1810–1815 (2007).
Weber, J. S. et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J. Clin. Oncol. 26, 5950–5956 (2008).
Ansell, S. M. et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin. Cancer Res. 15, 6446–6453 (2009).
O'Day, S. J. et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann. Oncol. 21, 1712–1717 (2010).
Hersh, E. M. et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Invest. New Drugs 29, 489–498 (2011).
Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010).
Di Giacomo, A. M. et al. Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy). Cancer Immunol. Immunother. 60, 467–477 (2011).
Min, L., Vaidya, A. & Becker, C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur. J. Endocrinol. 164, 303–307 (2011).
Borodic, G., Hinkle, D. M. & Cia, Y. Drug-induced graves disease from CTLA-4 receptor suppression. Ophthal. Plast. Reconstr Surg. 27, e87–e88 (2011).
Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).
Sanderson, K. et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J. Clin. Oncol. 23, 741–750 (2005).
Bednarczuk, T., Gopinath, B., Ploski, R. & Wall, J. R. Susceptibility genes in Graves' ophthalmopathy: searching for a needle in a haystack? Clin. Endocrinol. (Oxf.) 67, 3–19 (2007).
Han, S. et al. CTLA4 polymorphisms and ophthalmopathy in Graves' disease patients: association study and meta-analysis. Hum. Immunol. 67, 618–626 (2006).
Sinclair, D. Clinical and laboratory aspects of thyroid autoantibodies. Ann. Clin. Biochem. 43, 173–183 (2006).
Spain, L., Diem, S. & Larkin, J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat. Rev. 44, 51–60 (2016).
Sarkar, S. D. Benign thyroid disease: what is the role of nuclear medicine? Semin. Nucl. Med. 36, 185–193 (2006).
Min, L. & Ibrahim, N. Ipilimumab-induced autoimmune adrenalitis. Lancet Diabetes Endocrinol. 1, e15 (2013).
Bacanovic, S., Burger, I. A., Stolzmann, P., Hafner, J. & Huellner, M. W. Ipilimumab-induced adrenalitis: a possible pitfall in 18F-FDG-PET/CT. Clin. Nucl. Med. 40, e518–e519 (2015).
Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).
Blank, C. et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 64, 1140–1145 (2004).
Motzer, R. J. et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II Trial. J. Clin. Oncol. 33, 1430–1437 (2015).
Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).
National Cancer Institute. Common terminology criteria for adverse events (CTCAE) version 4.0. NCI https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5×11.pdf (2009).
Rizvi, N. A. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015).
Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).
Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
McDermott, D. F. et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J. Clin. Oncol. 34, 833–842 (2016).
Orlov, S., Salari, F., Kashat, L. & Walfish, P. G. Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J. Clin. Endocrinol. Metab. 100, 1738–1741 (2015).
Narita, T. et al. Serological aggravation of autoimmune thyroid disease in two cases receiving nivolumab. J. Dermatol. 43, 210–214 (2016).
Verma, I., Modi, A., Tripathi, H. & Agrawal, A. Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of the lung. BMJ Case Rep. http://dx.doi.org/10.1136/bcr-2015-213692 (2016).
Nielsen, C. H., Hegedus, L. & Leslie, R. G. Autoantibodies in autoimmune thyroid disease promote immune complex formation with self antigens and increase B cell and CD4+ T cell proliferation in response to self antigens. Eur. J. Immunol. 34, 263–272 (2004).
Gaudy, C. et al. Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care 38, e182–e183 (2015).
Mellati, M. et al. Anti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care 38, e137–e138 (2015).
Hughes, J. et al. Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy. Diabetes Care 38, e55–e57 (2015).
Martin-Liberal, J. et al. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol. Immunother. 64, 765–767 (2015).
Prokunina, L. et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat. Genet. 32, 666–669 (2002).
Nielsen, C., Hansen, D., Husby, S., Jacobsen, B. B. & Lillevang, S. T. Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes. Tissue Antigens 62, 492–497 (2003).
Prokunina, L. et al. Association of the PD-1.3A allele of the PDCD1 gene in patients with rheumatoid arthritis negative for rheumatoid factor and the shared epitope. Arthritis Rheum. 50, 1770–1773 (2004).
Antonia, S. et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 17, 299–308 (2016).
Messal, N., Serriari, N. E., Pastor, S., Nunes, J. A. & Olive, D. PD-L2 is expressed on activated human T cells and regulates their function. Mol. Immunol. 48, 2214–2219 (2011).
Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).
Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
Korman, A. et al. Activity of anti-PD-1 in murine tumor models: role of “host” PD-L1 and synergistic effect of anti-PD-1 and anti-CTLA-4. J. Immunol. 178 (Suppl.), S82 (2007).
Larkin, J. et al. 3303 Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naïve patients with advanced melanoma (MEL) (CheckMate 067). Eur. J. Cancer 51, S664–S665 (2015).
Weber, J. S. et al. Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multipeptide vaccine for resected stages IIIC and IV melanoma. J. Clin. Oncol. 27 (Suppl.), 9023 (2009).
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D.J.B. and M.G. researched data for the article, made substantial contribution to discussion of the content, wrote, reviewed and edited the manuscript before submission. J.D.W. made substantial contribution to discussion of the content, and reviewed and edited the manuscript before submission. L.M.R. researched data for the article and wrote the manuscript.
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J.D.W. is a consultant and receives research funding from AstraZeneca, Bristol-Myers Squibb, Genentech, Merck and Medimmune. M.G. has been a consultant for AstraZeneca and Bristol-Myers Squibb. D.J.B. and L.M.R. declare no competing interests.
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Byun, D., Wolchok, J., Rosenberg, L. et al. Cancer immunotherapy — immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol 13, 195–207 (2017). https://doi.org/10.1038/nrendo.2016.205
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DOI: https://doi.org/10.1038/nrendo.2016.205
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