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  • Review Article
  • Published:

Immune-checkpoint inhibitors: long-term implications of toxicity

Nature Reviews Clinical Oncology volume 19, pages 254–267 (2022)Cite this article

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Abstract

The development of immune-checkpoint inhibitors (ICIs) has heralded a new era in cancer treatment, enabling the possibility of long-term survival in patients with metastatic disease, and providing new therapeutic indications in earlier-stage settings. As such, characterizing the long-term implications of receiving ICIs has grown in importance. An abundance of evidence exists describing the acute clinical toxicities of these agents, although chronic effects have not been as well catalogued. Nonetheless, emerging evidence indicates that persistent toxicities might be more common than initially suggested. While generally low-grade, these chronic sequelae can affect the endocrine, rheumatological, pulmonary, neurological and other organ systems. Fatal toxicities also comprise a diverse set of clinical manifestations and can occur in 0.4–1.2% of patients. This risk is a particularly relevant consideration in light of the possibility of long-term survival. Finally, the effects of immune-checkpoint blockade on a diverse range of immune processes, including atherosclerosis, heart failure, neuroinflammation, obesity and hypertension, have not been characterized but remain an important area of research with potential relevance to cancer survivors. In this Review, we describe the current evidence for chronic immune toxicities and the long-term implications of these effects for patients receiving ICIs.

Key points

  • Immune-checkpoint inhibitors (ICIs) produce durable responses in a growing number of patients with metastatic cancer, and are being used increasingly in (neo)adjuvant settings.

  • Although acute toxicities are more common, chronic immune-related adverse events (irAEs) are increasingly recognized, and can affect up to 40% of patients.

  • Chronic irAEs are mostly classed as endocrine or rheumatological, but can affect a diverse array of organs.

  • Other issues with long-term relevance include fatal irAEs (which can occur in 0.4–1.2% of patients), and rechallenge after severe irAEs.

  • ICIs could also affect other immune-mediated processes (such as atherosclerosis or neuroinflammation), although more studies are needed.

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Fig. 1: Proposed mechanisms of immune-related adverse events.
Fig. 2: Mechanisms of chronic immune-checkpoint inhibitor-mediated toxicity.
Fig. 3: Possible frequencies of chronic immune-checkpoint inhibitor-induced toxicities.
Fig. 4: Time course and potential importance of key issues throughout the course of treatment with immune-checkpoint inhibitors.

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Acknowledgements

The work of D.B.J. is funded by the Susan and Luke Stephens Directorship, the James C. Bradford Melanoma Fund, and the Van Stephenson Cancer Memorial Fund.

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Authors and Affiliations

  1. Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA

    Douglas B. Johnson, Caroline A. Nebhan, Javid J. Moslehi & Justin M. Balko

  2. Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    Javid J. Moslehi

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All authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Correspondence to Douglas B. Johnson.

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Competing interests

D.B.J. has acted as a consultant and/or advisor for BMS, Catalyst, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer and Targovax, and receives research funding from BMS and Incyte. D.B.J. and J.J.M. have a patent pending for use of abatacept to reverse ICI toxicities. D.B.J. and J.M.B. have a patent pending for use of MHC II as a biomarker for ICI response. J.M.B. receives research funding from Genentech and Incyte. C.A.N. and J.J.M. declare no competing interests.

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Johnson, D.B., Nebhan, C.A., Moslehi, J.J. et al. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol 19, 254–267 (2022). https://doi.org/10.1038/s41571-022-00600-w

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