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

Brendan L Mangan ¹, Renee K McAlister ¹, Justin M Balko ², Douglas B Johnson ³, Javid J Moslehi ³, Andrew Gibson ⁴, Elizabeth J Phillips ³

Affiliations

¹ Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, USA.
² Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, WA, Australia.

PMID: 32543711
113 References
14 citations

Abstract

Immune checkpoint inhibitors have emerged as a revolutionary treatment option for patients with various types of malignancy. Although these agents afford a significant improvement in outcomes for melanoma and other previously untreatable malignancies, their novel mechanism of action may predispose patients to immune-related adverse effects (irAEs). In the tumour neoantigen environment, these irAEs are due to the activation of the immune system by the blockade of suppressive checkpoints, leading to increases in T-cell activation and proliferation. IrAEs have been reported in almost any organ and at any point in time, even months to years after discontinuation of therapy. Certain populations with distinct physiological changes, genetic risk factors, and specific antigen exposures may be more highly predisposed to develop irAEs. This review discusses the incidence and mechanisms of irAEs and the relationship between host factors and irAE occurrence.

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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Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. Julie R Brahmer, Charles G Drake, +17 authors, Suzanne L Topalian. less J Clin Oncol, 2010 Jun 03; 28(19). PMID: 20516446 Free PMC article. Highly Cited.
Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Jeryl Villadolid, Asim Amin. Transl Lung Cancer Res, 2015 Dec 03; 4(5). PMID: 26629425 Free PMC article. Highly Cited. Review.

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Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy. Brendan L Mangan, Renee K McAlister, +4 authors, Elizabeth J Phillips. less Br J Clin Pharmacol, 2020 Jun 17; 86(9). PMID: 32543711 Free PMC article. Review.
Taking the brake off the immune system: Hypotheses, trials, tribulations, and the evolving discipline of clinical immunopharmacology. Jennifer H Martin, Lionel D Lewis. Br J Clin Pharmacol, 2020 Aug 10; 86(9). PMID: 32770557 Free PMC article.
Essential Oils and Their Main Chemical Components: The Past 20 Years of Preclinical Studies in Melanoma. Marta Di Martile, Stefania Garzoli, Rino Ragno, Donatella Del Bufalo. Cancers (Basel), 2020 Sep 20; 12(9). PMID: 32948083 Free PMC article. Review.
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Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms. Javid Moslehi, Andrew H Lichtman, +2 authors, Arlene H Sharpe, Lorenzo Galluzzi, Richard N Kitsis. less J Clin Invest, 2021 Mar 02; 131(5). PMID: 33645548 Free PMC article. Review.
Immune Check Point Inhibitors and Immune-Related Adverse Events in Small Cell Lung Cancer. Wanting Hou, Xiaohan Zhou, Cheng Yi, Hong Zhu. Front Oncol, 2021 Apr 06; 11. PMID: 33816235 Free PMC article. Review.
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