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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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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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.
- Hashimoto’s thyroiditis
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.
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.
A complex of three regulatory proteins found in muscle that indicate heart damage when elevated.
- Guillain–Barré syndrome
An autoimmune condition in which there is ascending paralysis starting in the lower extremities.
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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