Review
. 2020 Jun; 86(9):1778-1789.
doi: 10.1111/bcp.14433.

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
  • 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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Oncologist, 2013 Jun 19; 18(6). PMID: 23774827    Free PMC article.
Highly Cited. Review.
Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial.
Frank Stephen Hodi, Vanna Chiarion-Sileni, +16 authors, Jedd D Wolchok.
Lancet Oncol, 2018 Oct 27; 19(11). PMID: 30361170
Highly Cited.
CTLA-4 ablation and interleukin-12 driven differentiation synergistically augment cardiac pathogenicity of cytotoxic T lymphocytes.
Victoria A Love, Nir Grabie, +3 authors, Andrew Lichtman.
Circ Res, 2007 Jun 16; 101(3). PMID: 17569889
NK Cell Dysfunction and Checkpoint Immunotherapy.
Jiacheng Bi, Zhigang Tian.
Front Immunol, 2019 Sep 26; 10. PMID: 31552017    Free PMC article.
Review.
The T cell repertoire in tumors overlaps with pulmonary inflammatory lesions in patients treated with checkpoint inhibitors.
Heinz Läubli, Viktor H Koelzer, +6 authors, Alfred Zippelius.
Oncoimmunology, 2018 Jan 09; 7(2). PMID: 29308309    Free PMC article.
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
Tony S K Mok, Yi-Long Wu, +13 authors, KEYNOTE-042 Investigators.
Lancet, 2019 Apr 09; 393(10183). PMID: 30955977
Highly Cited.
Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy.
Brendan L Mangan, Renee K McAlister, +4 authors, Elizabeth J Phillips.
Br J Clin Pharmacol, 2020 Jun 17; 86(9). PMID: 32543711    Free PMC article.
Review.
Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.
Joe-Elie Salem, Ali Manouchehri, +10 authors, Javid J Moslehi.
Lancet Oncol, 2018 Nov 18; 19(12). PMID: 30442497    Free PMC article.
Highly Cited.
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.
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.
Evolving insights into the mechanisms of toxicity associated with immune checkpoint inhibitor therapy.
Brendan L Mangan, Renee K McAlister, +4 authors, Elizabeth J Phillips.
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.
Intensified immunosuppressive therapy in patients with immune checkpoint inhibitor-induced myocarditis.
Jennifer Cautela, Sarah Zeriouh, +7 authors, Franck Thuny.
J Immunother Cancer, 2020 Dec 11; 8(2). PMID: 33298621    Free PMC article.
Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms.
Javid Moslehi, Andrew H Lichtman, +2 authors, Richard N Kitsis.
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.
Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions.
Yueran Li, Pooja Deshpande, +3 authors, Elizabeth J Phillips.
Front Genet, 2021 May 04; 12. PMID: 33936169    Free PMC article.
Review.
Lymph Node Immune Profiles as Predictive Biomarkers for Immune Checkpoint Inhibitor Response.
Emily F Goode, Evanthia T Roussos Torres, Sheeba Irshad.
Front Mol Biosci, 2021 Jun 19; 8. PMID: 34141724    Free PMC article.
Review.
Role of pharmacogenomics in T-cell hypersensitivity drug reactions.
Rebecca J Hertzman, Pooja Deshpande, Andrew Gibson, Elizabeth J Phillips.
Curr Opin Allergy Clin Immunol, 2021 May 28; 21(4). PMID: 34039850    Free PMC article.
Review.
Impact of concomitant medication on clinical outcomes in patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors: A retrospective study.
Kaho Miura, Yoshiyuki Sano, +12 authors, Kazuhiko Hanada.
Thorac Cancer, 2021 May 15; 12(13). PMID: 33990133    Free PMC article.
Immune Checkpoint Inhibitors in the Management of Urothelial Carcinoma.
Aakash Patel, Daniel I Bisno, +4 authors, Eric A Singer.
J Cancer Immunol (Wilmington), 2021 Jul 16; 3(2). PMID: 34263255    Free PMC article.
Novel insights into the pathogenesis and treatment of NRAS mutant melanoma.
Jeffrey Zhao, Carlos Galvez, +2 authors, Jeffrey A Sosman.
Expert Rev Precis Med Drug Dev, 2021 Sep 07; 6(4). PMID: 34485698    Free PMC article.
Adverse Effects and Toxicity of Immune Checkpoint Inhibitors For Patients With Urothelial Carcinoma.
Di Wang, Kai Sun, +5 authors, Jitao Wu.
Front Pharmacol, 2021 Dec 07; 12. PMID: 34867321    Free PMC article.
Review.
Crossed Pathways for Radiation-Induced and Immunotherapy-Related Lung Injury.
Zengfu Zhang, Jialin Zhou, +4 authors, Dawei Chen.
Front Immunol, 2021 Dec 21; 12. PMID: 34925345    Free PMC article.
Review.