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.
Understanding adverse events of immunotherapy: A mechanistic perspective
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.
- Views Icon Views
- Share Icon Share
- Search Site
Kelly P. Burke, Stephanie Grebinoski, Arlene H. Sharpe, Dario A.A. Vignali; Understanding adverse events of immunotherapy: A mechanistic perspective. J Exp Med 4 January 2021; 218 (1): e20192179. doi: https://doi.org/10.1084/jem.20192179
Download citation file: