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Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy

Brendan L Mangan1, Renee K McAlister1, Justin M Balko2,3,4

  • 1Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, USA.

British Journal of Clinical Pharmacology
|June 17, 2020
PubMed

Insights

Immune checkpoint inhibitors treat cancer but can cause immune-related adverse effects (irAEs) due to immune system activation. This review explores irAE incidence, mechanisms, and patient factors influencing their occurrence.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Immune checkpoint inhibitors (ICIs) represent a breakthrough in cancer therapy, significantly improving outcomes for various malignancies.
  • The mechanism of action of ICIs involves immune system activation, which can lead to unintended immune-related adverse effects (irAEs).

Purpose of the Study:

  • To review the incidence and underlying mechanisms of immune-related adverse effects (irAEs) associated with immune checkpoint inhibitor therapy.
  • To explore the relationship between host factors and the predisposition to developing irAEs.

Main Methods:

  • Literature review of studies on immune checkpoint inhibitors and their associated adverse events.
  • Analysis of mechanisms driving T-cell activation and proliferation in the context of irAEs.
  • Examination of patient-specific factors (physiological, genetic, antigen exposure) linked to irAE occurrence.

Main Results:

  • Immune-related adverse effects (irAEs) can manifest in virtually any organ and at any time, even long after therapy cessation.
  • The development of irAEs is linked to the enhanced T-cell activation and proliferation resulting from ICI blockade of suppressive checkpoints.
  • Certain patient populations exhibit a higher predisposition to irAEs due to unique physiological, genetic, or antigen exposure profiles.

Conclusions:

  • Immune checkpoint inhibitors, while effective cancer treatments, carry a risk of immune-related adverse effects.
  • Understanding the mechanisms and host factors associated with irAEs is crucial for managing patients receiving ICI therapy.
  • Further research into patient stratification and risk prediction for irAEs is warranted.
Keywords:
cytotoxic T-lymphocyte antigen-4, immune checkpoint inhibitors, immune-related adverse effects, immunotherapy, programmed cell death 1, programmed cell death ligand 1

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