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Review
. 2019 Jan 14;191(2):E40-E46.
doi: 10.1503/cmaj.180870.

Adverse events associated with immune checkpoint inhibitor treatment for cancer

Khashayar Esfahani  1 , Nicholas Meti  2 , Wilson H Miller Jr  2 , Marie Hudson  1
Affiliations
Review

Adverse events associated with immune checkpoint inhibitor treatment for cancer

Khashayar Esfahani et al. CMAJ. .
No abstract available

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Conflict of interest statement

Competing interests: Marie Hudson reports receiving a grant from Bristol-Myers Squibb, outside the submitted work. Khashayar Esfahani reports receiving speaker’s fees from Bristol-Myers Squibb, outside the submitted work. Wilson Miller reports receiving grants from Bristol-Myers Squibb, Merck, Roche, Novartis, AstraZeneca, Amgen, Bayer, MedImmune and GlaxoSmithKline, outside the submitted work, as well as personal fees from Bristol-Myers Squibb, Merck, Roche, Novartis, Amgen and GlaxoSmithKline. No other competing interests were declared.

Figures

Figure 1:
Figure 1:
A) Antigen presenting cells (APC), such as dendritic cells (DC), scout the human body, sampling different antigens, including tumour-associated antigens, which are then processed and presented through the major histocompatibility (MHC) complex. In a priming phase that takes place in peripheral lymph nodes, APC educate and activate antigen-specific T cells. T cell activation is kept in check by cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), a negative regulator of T-cell function. This negative signal can be blocked by CTLA-4 inhibitors (i.e., ipilimumab), allowing ongoing T-cell activation and migration to the tumour bed. B) Activated T cells also express programmed cell death 1 (PD1), and its ligands, PDL1 and PDL2, are commonly expressed on APC. PD1 and PDL1/PDL2 interaction also inhibits T-cell responses. Tumours can express PDL1 and PDL2 receptors, and engagement of these receptors with the PD1 receptor on T cells turns off T cells and allows tumours to escape destruction. These immune checkpoints can be blocked by PD-1 inhibitors (i.e., nivolumab, pembrolizumab) or PDL-1 inhibitors (i.e., atezolizumab, avelumab and durvalumab). CTLA-4 inhibition results in more widespread and severe immune-related adverse events (irAE), as it regulates T-cell function early in the immunity cycle. Blocking PD-1, on the other hand, is more specific to the tumour microenvironment and, in general, results in less widespread and severe irAE. Note: CD28 = cluster of differentiation 28, TCR = T-cell receptor.
Figure 2:
Figure 2:
Organs affected by and manifestations of immune-related adverse events.
Figure 3:
Figure 3:
Summarized management strategies for immune-related adverse events (irAE), adapted from the latest American Society of Clinical Oncology (ASCO) guideline. The only exception to this algorithm is the management of endocrine irAE, where physiologic hormone replacement, rather than high-dose steroid use, is recommended for any grade irAE. *High-dose steroids, defined as 1 mg/kg, or oral prednisone or 2 mg/kg of intravenous solumedrol. Note: CTCAE = Common Terminology Criteria for Adverse Events, ESMO = European Society for Medical Oncology, ICI = immune checkpoint inhibitors.
See this image and copyright information in PMC

References

    1. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015;33:1889–94. - PMC - PubMed
    1. Gettinger S, Horn L, Jackman D, et al. Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study. J Clin Oncol 2018;36:1675–84. - PubMed
    1. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 2011;331:1565–70. - PubMed
    1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252–64. - PMC - PubMed
    1. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018;359:1350–5. - PMC - PubMed

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