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  • Review Article
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Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies

Nature Reviews Drug Discovery volume 21, pages 495–508 (2022)Cite this article

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Abstract

The immune-related adverse events associated with treatment with immune checkpoint inhibitors result in significant morbidity for patients as well as considerable cost to the health-care system, and can limit the use of these beneficial drugs. Understanding the mechanisms of these side effects and how they can be separated from the antitumour effects of immune checkpoint inhibitors, as well as identifying biomarkers that predict the development of immune-related toxicities, will facilitate the conduct of trials to limit their onset and improve patient outcomes. In this Review, we discuss the different types of immune-related adverse events and how their treatment and identification of possible predictive biomarkers may shed light on their mechanisms, and describe possible strategies and targets for prophylactic and therapeutic intervention to mitigate them.

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Fig. 1: Different mechanisms drive immune-related adverse events.

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Authors and Affiliations

  1. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ryan J. Sullivan

  2. Laura and Isaac Perlmutter Comprehensive Cancer Center, NYU Grossman School of Medicine, New York, NY, USA

    Jeffrey S. Weber

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The authors contributed equally to all aspects of the article.

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Correspondence to Jeffrey S. Weber.

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Competing interests

J.S.W. is a consultant for Merck, Genentech, AstraZeneca, Pfizer, Regeneron, GSK, Alkermes, Novartis, Celldex, Incyte and EMD Serono. He is a member of the advisory board for BMS, and holds equity in CytoMx, Biond, Neximmune and Immunimax. He is also part of the scientific advisory boards for Celldex, CytoMx, Incyte, Biond, Neximmune and Sellas. J.S.W.’s laboratory has received research support from BMS, Merck, GSK, Novartis, Moderna and AstraZeneca. Moffitt Cancer Center filed a patent on an ipilimumab biomarker and a TIL growth method, in which J.S.W. has been named, as well as in a PD1 biomarker patent by Biodesix. R.J.S. declares no competing interests.

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Glossary

Clonotype

Unique sequence of a T cell receptor chain

Tertiary lymphoid structures

Lymph node-like structures found within the stroma of some tumours.

Bullous pemphigoid

An autoimmune skin disease marked by formation of bullae or blisters, urticarial lesions (hives) and itching due to an immune reaction against desmosomes responsible for anchoring the epidermis and the dermis.

Stevens–Johnson syndrome/toxic epidermal necrolysis

A disorder of the skin and mucous membranes that causes the skin to peel off and die.

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Also known as chronic lymphocytic thyroiditis. An autoimmune condition of the thyroid that presents initially with acute hyperthyroidism and then evolves to a ‘burnt-out’ thyroid with hypothyroidism.

Cholestasis

Slowing of the flow of bile from the liver.

ST segment

Flat segment of the electrocardiogram between the end of the S wave and the beginning of the T wave.

Troponin

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Guillain–Barré syndrome

An autoimmune condition in which there is ascending paralysis starting in the lower extremities.

Autoantibodies

Antibodies that react with normal self-tissue and are often a marker for activity of various autoimmune diseases and themselves can cause pathology.

Time-delay bias

An overestimation of survival or another parameter due to an excess of cases detected later in the course of a disease.

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Sullivan, R.J., Weber, J.S. Immune-related toxicities of checkpoint inhibitors: mechanisms and mitigation strategies. Nat Rev Drug Discov 21, 495–508 (2022). https://doi.org/10.1038/s41573-021-00259-5

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