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Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management

Key Points

  • Immune checkpoint inhibitors promote an antitumour immune response by blocking signalling via either the cytotoxic T lymphocyte antigen 4 (CTLA4) pathway or the programmed cell death protein 1 (PD1) pathway

  • Their use can result in immune-related adverse events, including the development of gastrointestinal inflammation, which shares certain clinicopathological features with IBD

  • In suspected cases of persistent mild or moderate-to-severe immune checkpoint inhibitor-induced gastrointestinal inflammation, endoscopic and histological investigation should be arranged to confirm the diagnosis, and other possible causes of symptoms should be excluded

  • Corticosteroids should be used in the first instance to manage inflammation, and in patients who are refractory to corticosteroids, the addition of infliximab or vedolizumab should be considered

Abstract

Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies, including melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin lymphoma. Their use in a range of other indications, such as gastrointestinal and head and neck cancer, is currently under investigation. The number of agents included in this drug group is increasing, as is their use. Although they have the potential to improve the treatment of advanced malignancies, they are also associated with a substantial risk of immune-related adverse events. The incidence of gastrointestinal toxicity associated with their use is second only in frequency to dermatological toxicity. Thus, gastroenterologists can expect to be increasingly frequently consulted by oncologists as part of a multidisciplinary approach to managing toxicity. Here, we describe this novel group of agents and their mechanisms of action. We review the manifestations of gastrointestinal toxicity associated with their use so that it can be recognized early and diagnosed accurately. We also discuss the proposed mechanisms underlying this toxicity and describe an algorithmic and, wherever possible, evidence-based approach to its management.

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Figure 1: The role of CTLA4 and PD1 in T cell activation.
Figure 2: Gastrointestinal toxicity observed among selected randomized controlled trials of immune checkpoint inhibitor agents.
Figure 3: Suggested algorithm for the management of immune checkpoint inhibitor-associated gastrointestinal toxicity.

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Authors

Contributions

All authors made substantial contributions to discussion of content and reviewed and/or edited the manuscript before submissions. M.A.S. and P.P. researched the contributing data and wrote the article.

Corresponding author

Correspondence to Peter M. Irving.

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Competing interests

M.A.S. has received advisory fees from Hospira and lecture fees from Falk, Hospira, Janssen, MSD and Takeda. S.P. has received advisory fees from Amgen, MSD and Roche and lectures fees from Bristol–Myers Squibb and MSD. N.P. has received advisory fees from AbbVie, Allergan, Debiopharm International, Ferring and Vifor Pharma and lectures fees from Allergan, Falk, Janssen, Tillotts and Takeda. P.M.I. has received advisory fees from AbbVie, Genentech, Hospira, Janssen, MSD, Pharmacosmos, Samsung Bioepis, VH2, Vifor Pharma, Takeda, Topivert and Warner Chilcott, lecture fees from AbbVie, Falk, Ferring and Warner Chilcott and financial support for research from MSD and Takeda. P.P. declares no competing interests.

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Glossary

Antigen-presenting cells

(APCs). Cells that capture, process and display antigens (such as those from microorganisms, environmental toxins and/or tumour neo-antigens) to lymphocytes; they also express co-stimulatory signals (that is, CD80/CD86 expression), which are necessary for lymphocyte activation (proliferation and effector function).

Tolerance

A state in which the adaptive immune system does not respond to an antigen. During T cell development in the thymus, cells that recognize self-antigens are deleted (central tolerance), a process that contributes to self-tolerance, a homeostatic attribute of the adaptive immune system.

Immune checkpoint inhibitors

Drugs that promote an antitumour immune response by blocking signalling via either the cytotoxic T lymphocyte antigen 4 (CTLA4) pathway or the programmed cell death 1 (PD1) pathway.

Co-stimulatory pathway

The necessary, additional activating signal to T cell receptor (CD3) engagement with antigen, which leads T cells towards proliferation and effector function.

Immunological synapse

The crosstalk interface for immune cells where, for example, the antigen presented by an antigen-presenting cell and its surface CD80 molecule engage a T cell through the T cell receptor and CD28, respectively.

Regulatory T cells

(Treg cells). Regulatory cells, usually defined as CD4+CD25+, that are characterized by the expression of the transcription factor forkhead box protein 3 (FOXP3). Through cytokine production (such as IL-10 and transforming growth factor-β (TGFβ)) and cellular interactions (that is, through cytotoxic T lymphocyte antigen 4 (CTLA4)), they suppress the responses of surrounding activated lymphocytes.

CD4+ T effector cells

T cells that, upon activation by an antigen-presenting cell, produce cytokines and drive inflammation. Activated naive cells turn to memory cells that can mount a response to the same antigen much more quickly.

Hypophysitis

An acute or chronic inflammation of the pituitary gland.

Patient-reported outcomes

(PROs). Health outcomes directly reported by the patients who experience them.

Acute abdomen

A rapid onset of severe symptoms that can indicate potentially life-threatening intra-abdominal pathology that requires urgent surgical intervention.

Small intestinal bacterial overgrowth

The presence of excessive bacteria in the small intestine, frequently implicated as the cause of chronic diarrhoea and malabsorption.

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Samaan, M., Pavlidis, P., Papa, S. et al. Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management. Nat Rev Gastroenterol Hepatol 15, 222–234 (2018). https://doi.org/10.1038/nrgastro.2018.14

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