Gastrointestinal and Hepatic Complications of Immune Checkpoint Inhibitors
- 2.2k Downloads
Purpose of Review
Gastrointestinal complications are very common in patients undergoing cancer treatment. Some of these complications can be life threatening and require prompt and appropriate diagnosis and treatment. The purpose of this review is to address luminal gastrointestinal and hepatic complications associated with a new class of anticancer drugs, immune checkpoint inhibitors (CPIs), and focuses on the identification, evaluation, and management of the complications associated with this class of drugs.
It is now recognized that immune checkpoint inhibitors are frequently associated with luminal GI side effects such as diarrhea and enterocolitis and hepatic complications such as hepatitis. While colitis associated with CPIs, to some extent, mimics that found in idiopathic inflammatory bowel disease, the complex interplay of genes, the environment, the immune system, and the microbiome make it difficult to fully differentiate these conditions clinically. CPI-induced hepatitis is most often associated with a pattern of hepatocellular injury with panlobular hepatitis. A variety of biomarkers have been proposed to predict an adverse response to CPIs and are under investigation. It has been proposed that alterations in the microbiome may impact the risk of developing colitis, and these studies are reviewed. In contrast to idiopathic chronic inflammatory bowel disease, CPI-induced colitis is often reversible if rapidly treated in accordance with the immune-mediated adverse reaction management guidelines. Treatment algorithms have been suggested but are, to some extent, empiric and based on algorithms for the treatment of idiopathic inflammatory bowel disorders.
CPIs may be associated with significant GI complications which impact their successful use in the treatment of neoplastic diseases. Much of what we currently know about the mechanisms and treatment of these complications is empiric and extrapolated from experience with idiopathic inflammatory bowel disease and other immune disorders. Current research focuses on understanding genetic predisposition and the role of the microbiome and identifying predictive risk markers for developing complications.
KeywordsCheckpoint inhibitors Immune modulation Toxicity Colitis Hepatitis CTLA-4 PD-1 Ipilimumab Microbiome
Thanks to Editor-in-Chief Joel Richter for the help in reviewing this paper.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 8.•• Marthey L, Mateus C, Mussini C, et al. Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J Crohn’s Colitis. 2016;10:395–401. This study provides common laboratory, endoscopic, and histologic findings associated with anti-CTLA-4 gastrointestinal adverse events.CrossRefGoogle Scholar
- 10.Gonzalez-Cao M, Boada A, Teixidó C, et al. Fatal gastrointestinal toxicity with ipilimumab after BRAF/MEK inhibitor combination in a melanoma patient achieving pathological complete response. Oncotarget 2016;7:56619–56627.Google Scholar
- 14.Berman D, Parker SM, Siegel J, et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun; 2010;10:11.Google Scholar
- 15.Ina K, Itoh J, Fukushima K, et al. Resistance of Crohn’s disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance. J Immunol. 2009;163:1081–90.Google Scholar
- 32.Carbognin L, Pilotto S, Milella M, et al. Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS ONE. 2015;10, e0130142.CrossRefPubMedPubMedCentralGoogle Scholar
- 36.• Shahabi V, Berman D, Chasalow SD, et al. Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events. J Transl. 2013;11:75. Alterations in a number of biomarkers have been correlated with both treatment efficacy and the development of gastrointestinal toxic events of immune checkpoint inhibitors. This paper suggests that gene expression profiling could play an important role in future treatment decisions and prevention of irAEs.CrossRefGoogle Scholar
- 39.• Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079–84. Understanding the role of the gut microbiota in CTLA-4 blockade is critical in both treatment efficacy and the development of adverse events. Certain commensals might serve as anticancer probiotics, while others might even antagonize anticancer efficacy.CrossRefPubMedPubMedCentralGoogle Scholar
- 45.Tobias L. A briefing report on autoimmune diseases and AARDA: past, present, and future. Eastpointe: American Autoimmune Related Diseases Association (AARDA) 2010.Google Scholar
- 46.Common Terminology Criteria for Adverse Events (CTCAE). Retrieved August 1, 2016, from http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 2010.
- 47.Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:559.CrossRefGoogle Scholar