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Cancer immunotherapy–related adverse events: causes and challenges

Abstract

Despite the success and ongoing promise of monoclonal antibody–targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint–targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.

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Funding

Professor BL Rapoport is supported by the Cancer Association of South Africa (CANSA) and the National Research Foundation (NRF) of South Africa.

Dr. I. Glezerman is supported by the NIH/NCI (Cancer Center Support Grant P30 CA008748)

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All of the authors contributed equally to the conceptualization of the manuscript; sections on immunological mechanisms were shared equally by AGB and RA, while BLR and DBJ provided clinical input and oversight. All of the authors provided critical appraisal of the manuscript and approve of its submission.

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Correspondence to Bernardo L. Rapoport.

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Conflict of interest

AB, RA, JC, TC, PG, DG, and VRS have no conflict of interest to declare. MC reports grants from Novartis, other from Neoleukin Therapeutics, personal fees from Partner Therapeutics, personal fees from Tillotts Pharma, and grants from Genentech, outside the submitted work. MG reports other from Bristol Myers Squibb (BMS) and other from AstraZeneca, outside the submitted work. IG reports other from Pfizer Inc and personal fees from CytomX Inc, outside the submitted work. DBJ reports other from Array Biopharma, grants and other from BMS, grants from Incyte, other from Jansen, other from Merck, and other from Novartis, outside the submitted work. In addition, DBJ has a patent co-inventor on use of CTLA-4 agonist for IAEs pending. BLR reports personal fees and other from Merck and Co, grants, personal fees, and other from BMS; grants, personal fee,s and other from Roche South Africa; and personal fees and other from AstraZeneca, during the conduct of the study. MSA reports personal fees from Gilead, grants from Pfizer, and personal fees from Abbvie, outside the submitted work. All work with these entities has ended.

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Blidner, A.G., Choi, J., Cooksley, T. et al. Cancer immunotherapy–related adverse events: causes and challenges. Support Care Cancer 28, 6111–6117 (2020). https://doi.org/10.1007/s00520-020-05705-5

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  • DOI: https://doi.org/10.1007/s00520-020-05705-5

Keywords

  • Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)
  • Ipilimumab
  • Microbiome
  • Nivolumab
  • Programmed cell death protein 1 (PD-1)
  • Regulatory T lymphocytes (Tregs)