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Review
. 2021 Jan 4;218(1):e20192179.
doi: 10.1084/jem.20192179.

Understanding adverse events of immunotherapy: A mechanistic perspective

Kelly P Burke #  1   2   3 , Stephanie Grebinoski #  4   5 , Arlene H Sharpe  2   3   6 , Dario A A Vignali  4   7   8
Affiliations
Review

Understanding adverse events of immunotherapy: A mechanistic perspective

Kelly P Burke et al. J Exp Med. .

Abstract

The treatment of many cancers has been revolutionized by immune checkpoint blockade (ICB) as a standard-of-care therapeutic. Despite many successes, a large proportion of patients treated with ICB agents experience immune-related adverse events (irAEs) in the form of clinical autoimmunity, ranging from mild to life threatening, that can limit cancer treatment. A mechanistic understanding of these irAEs is required to better treat or prevent irAEs and to predict those patients who are susceptible to irAEs. We propose several mechanisms that may contribute to the generation of irAEs: (1) preexisting susceptibility to autoimmunity, (2) aberrant presentation of "self" by the tumor, and (3) loss of tolerance driven by the tumor or tissue microenvironment.

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Conflict of interest statement

Disclosures: A.H. Sharpe reported grants from NIH P01 AI108545 and grants from 2P50CA127003-11A1 during the conduct of the study; personal fees from Surface Oncology, Sqz Biotech, Selecta, Elstar, and Elpiscience; "other" from Monopteros; and grants from Novartis, Merck, Roche, Ipsen, UCB, and Quark Ventures outside the submitted work. In addition, A.H. Sharpe had a patent number 7,432,059 with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis); a patent number 7,722,868 with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis); a patent number 8,652,465 licensed (Roche); a patent number 9,457,080 licensed (Roche); a patent number 9,683,048 licensed (Novartis); a patent number 9,815,898 licensed (Novartis); a patent number 9,845,356 licensed (Novartis); a patent number 10,202,454 licensed (Novartis); a patent number 10,457,733 licensed (Novartis); a patent number 9,580,684 issued (none); a patent number 9,988,452 issued (none); and a patent number 10,370,446 issued (none). A.H. Sharpe is on the scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center, and is a Scientific Editor for the Journal of Experimental Medicine. D.A.A. Vignali reported grants from BMS, Astellas/Potenza, and Tizona outside the submitted work. In addition, D.A.A. Vignali had a patent to BMS with royalties paid (St Jude and JHU) and a patent to Astellas/Potenza with royalties paid (St Jude). D.A.A. Vignali also reports the following disclosures: "cofounder and stock holder: Novasenta, Tizona and Potenza; stock holder: Oncorus and Werewolf; patents licensed and royalties: Astellas, BMS; scientific advisory board member: Tizona, Werewolf, and F-Star; consultant: Astellas, BMS, Almirall, Incyte, Bicara; research funding: BMS, Astellas, and Novasenta." No other disclosures were reported.

Figures

Figure 1.
Figure 1.
There are several possible mechanisms contributing to irAEs in response to ICB. Importantly, these may occur distal to the tumor, in the periphery, or within the TME. It is still unclear which mechanism, if any, is the main driver of irAEs or to what degree interplay of these mechanisms contributes to disease. As irAEs are a critical limitation to cancer immunotherapy, understanding these mechanisms and how to prevent them is essential to the future of cancer immunotherapeutics.
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