Review Article | Published:

Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance


Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.

Key points

  • The frequency of immune-related adverse events (irAEs) is dependent on the agents used, exposure time and the administered dose but also on the patient’s intrinsic risk factors; conversely, the timing of appearance is often dictated by the affected organ systems.

  • High-risk patients receiving immune-checkpoint inhibitors (ICIs) should be regularly monitored for treatment-related complications by specialized multidisciplinary teams, ideally using a personalized surveillance strategy.

  • The application of formal contraindications to the use of ICIs among patients with a high risk of irAEs is not supported by well-founded scientific evidence.

  • In patients with severe and/or steroid-refractory irAEs, a biopsy sample should be obtained and investigated for infiltrating immune cells in order to enable the selection of novel biological agents targeting key inflammatory mediators.

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F.M. acknowledges the support of the Personalized Health and Related Technologies (PHRT) strategic focus area of the Swiss Federal Institutes of Technology (ETH) Domain and the Swiss Personalized Health Network (SPHN) initiative of the Swiss Academy of Medical Sciences (project no. 2017-407). The work of G.P.S. is partly supported by a 2016 Leenaards Foundation Fellowship for Academic Advancement in Clinical Medicine. The authors thank R. Guindon for his help in the conception of the figures.

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F.M. and M.O. researched data for this manuscript. F.M., J.A.T. and M.O. discussed manuscript content. All authors wrote the manuscript. F.M., G.P.S. and M.O. edited and/or reviewed the manuscript before submission.

Correspondence to Michel Obeid.

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S.P. has received education grants from and provided consultation, attended advisory boards and/or provided lectures for the following organizations: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche, Janssen, Merck Serono, Merck Sharp and Dohme, Novartis, Pfizer, Regeneron and Takeda. All other authors declare no competing interests.

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Fig. 1: Kinetics of main irAEs.
Fig. 2: The spectrum of irAEs by affected organ or organs.