Immune Checkpoint Inhibitor-Related Hypophysitis and Endocrine Dysfunction

Clinical Review

M.N Joshi; B.C. Whitelaw; M.T.P. Palomar; Y. Wu; P.V. Carroll

Disclosures

Clin Endocrinol. 2016;85(3):331-339. 

In This Article

Abstract and Introduction

Abstract

Immune checkpoint inhibitors are a new and effective class of cancer therapy, with ipilimumab being the most established drug in this category. The drugs' mechanism of action includes promoting the effector T cell response to tumours and therefore increased autoimmunity is a predictable side effect. The endocrine effects of these drugs include hypophysitis and thyroid dysfunction, with rare reports of adrenalitis. The overall incidence of hypophysitis with these medications is up to 9%. Primary thyroid dysfunction occurs in up to 15% of patients, with adrenalitis reported in approximately 1%. The mean onset of endocrine side effects is 9 weeks after initiation (range 5–36 weeks). Investigation and/or screening for hypophysitis requires biochemical and radiological assessment. Hypopituitarism is treated with replacement doses of deficient hormones. Since the endocrine effects of immune checkpoint inhibitors are classed as toxic adverse events, most authors recommend both discontinuation of the immune checkpoint inhibiting medication and 'high-dose' glucocorticoid treatment. However, this has been challenged by some authors, particularly if the endocrine effects can be managed (e.g. pituitary hormone deficiency), and the therapy is proving effective as an anticancer agent. This review describes the mechanism of action of immune checkpoint inhibitors and details the key clinical endocrine-related consequences of this novel class of immunotherapies.

Introduction

Recent advances in the understanding of immunology and cancer biology have resulted in the development of new classes of immune-modulatory therapy in the management of cancers. It is increasingly recognized that these new immune checkpoint inhibitors (e.g. ipilimumab) can cause significant dysfunction of the endocrine system.

Stimulatory T cell-mediated immune responses play a dominant role in the development of autoimmune diseases. Conversely, T cell-mediated inhibitory signalling pathways are understood to promote tumour proliferation by promoting tolerance to the tumour antigens. Leach et al.[1] first demonstrated the role of CTLA-4 (cytotoxic T lymphocyte antigen 4) as a molecular target for cancer immunotherapy. Since then, numerous T cell receptors such as PD-1 (programmed cell death protein-1), PDL1 (programmed cell death 1 ligand 1), LAG-3 (lymphocyte activation gene-3), TIM-3 (T-cell immunoglobulin mucin protein-3), GITR, and CD-137 have also been identified as potential targets for therapeutic drug development.[2] By blocking inhibitory signalling pathways, these drugs release immune responses against cancer self-antigens.

Ipilimumab (Yervoy; Bristol-Myers Squibb, New York, NY, USA) was one of the first immune checkpoint inhibitors to be approved for the treatment of cancer.[3] Recently, the FDA gave an accelerated approval to pembrolizumab (anti-PD-1 mAb; Keytruda; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA) and nivolumab (anti-PD-1 mAb, Opdivo, Bristol-Myers Squibb Company) in the management of unresectable metastatic malignant melanoma.[4,5] There are numerous other similar agents in early phase III, phase II clinical trials or preclinical studies including: tremelimumab (previously known as ticilimumab), pidilizumab, durvalumab, atezolizumab and avelumab.

Not unexpectedly, altering immune signalling pathways results in immune-related adverse events (IRAEs), which include dermatologic, gastrointestinal and endocrine toxicities. The different endocrine side effects seen with use of immune checkpoint inhibitors include hypophysitis with or without hypopituitarism, thyroid dysfunction and adrenalitis with associated hypoadrenalism have been comprehensively addressed in a 2013 review by Corsello et al.[6] We have written this article to help clinical endocrinologists understand the pathologic mechanisms and clinical features of immune checkpoint related endocrine disorders. It is important that clinical practitioners are able to recognize and manage endocrine dysfunction as consequence of the immuno-modulatory therapies.

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