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Endocrine toxicities of immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target two key signalling pathways related to T cell activation and exhaustion, by binding to and inhibiting cytotoxic T lymphocyte antigen 4 (CTLA4) or PD1 and its ligand PDL1. ICIs, such as nivolumab, pembrolizumab and ipilimumab, are approved for the treatment of numerous and diverse cancer types, in various combination regimens, and are now an established cornerstone of cancer therapeutics. Toxicities induced by ICIs are autoimmune in nature and are referred to as immune-related adverse events (irAEs); these events can affect any organ system in an unpredictable fashion. Importantly, irAEs can manifest as endocrinopathies involving the thyroid (hypothyroidism or thyrotoxicosis), pituitary (hypophysitis), adrenal glands (adrenal insufficiency) and pancreas (diabetes mellitus). These events are a frequent source of acute and persistent morbidity in patients treated with ICIs and can even be fatal. Over the past few years, there has been a growing understanding of the underlying pathogenesis of irAEs that has led to the development of more effective management strategies. Herein, we review the current understanding of the pathobiology, clinical manifestations and treatment approaches to endocrine toxicities arising from ICIs.

Key points

  • Immune checkpoint inhibitors (ICIs) are now a cornerstone of cancer therapies and are associated with long-term treatment responses, but they can also cause inflammatory toxicities in endocrine and other organs.

  • The most common ICI-induced endocrine toxicity is hypothyroidism, which occurs in 10–20% of treated patients, is often preceded by transient thyrotoxicosis, and usually persists after ICI therapy completion.

  • Hypopituitarism, which might co-occur with hypophysitis, is a condition nearly unique to ICI therapy, and is a clinically relevant cause of morbidity and rarely mortality.

  • ICI-associated diabetes mellitus (ICI-DM) occurs rarely (<1% of treated patients) but resembles type 1 diabetes mellitus, and patients can present with diabetic ketoacidosis.

  • Treatment for ICI-induced endocrinopathies involves hormone replacement therapy; patients can continue or resume their ICI once clinically stable.

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Fig. 1: Mechanisms of action of ICIs.
Fig. 2: Incidence of endocrine adverse events in patients treated with ICIs.
Fig. 3: Timing of onset for ICI-induced endocrinopathies.
Fig. 4: ICI-induced hypophysitis can affect multiple hormonal axes.

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Acknowledgements

The authors acknowledge the support of NIH/NCI K23 CA204726 (D.B.J.), NIH R01CA227481 (D.B.J.), DK20593 (A.C.P.), NIDDK T32DK007061 (J.J.W.), the Doris Duke Charitable Foundation, the James C. Bradford Jr. Melanoma Fund (D.B.J.), and the Melanoma Research Foundation (D.B.J.).

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Correspondence to Douglas B. Johnson.

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D.B.J. serves on advisory boards for Array Biopharma, Bristol Myers Squibb, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis and Oncosec, and receives research funding from Bristol Myers Squibb and Incyte. All other authors declare no competing interests.

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Nature Reviews Endocrinology thanks J.-J. Grob, M. Ryder and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Type II hypersensitivity reaction

An antibody-mediated immune reaction in which antibodies (IgG or IgM) are directed against cellular or extracellular matrix antigens with the resultant cellular destruction, functional loss or damage to tissues.

Complement

A system of small proteins that enhance phagocytic and antibody-mediated clearance of microorganisms.

Cosyntropin stimulation testing

Determination of adrenal cortisol secretory function by measuring cortisol levels at baseline and 30 or 60 minutes after injection of 250 µg of synthetic ACTH, cosyntropin.

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Wright, J.J., Powers, A.C. & Johnson, D.B. Endocrine toxicities of immune checkpoint inhibitors. Nat Rev Endocrinol 17, 389–399 (2021). https://doi.org/10.1038/s41574-021-00484-3

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