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This review addresses our current knowledge of immune-mediated colitis (IMC) and offers a practical guide to its management.
Due to the similarity in clinical, endoscopic, and histologic findings between IMC and inflammatory bowel disease (IBD), gastroenterologists have tailored their approach to IMC management to that of IBD.
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that augment the T-cell anti-tumor response of the immune system and have demonstrated their importance in the treatment of a wide range of malignancies. With the growing benefits of ICIs, there are immune-related adverse events (irAEs) that mirror many known autoimmune diseases. Diarrhea and IMC are the most common and severe irAEs noted. No standardized guidelines exist in the management of these irAEs.
• Wang Y, Abu-Sbeih H, Mao E, et al. Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J Immunother Cancer. 2018;6:37. https://doi.org/10.1186/s40425-018-0346-6 This study examines the link between immune-related adverse events and improved oncologic outcomes in patients on immunotherapy.
Postow M, Wolchok J. Toxicities associated with checkpoint inhibitor immunotherapy. In: Atkins MB, editor. UpToDate. Waltham: UpToDate; 2018.
•• Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–68. https://doi.org/10.1200/JCO.2017.77.6385 This study provides guidance on the management of immune-related adverse events in patients on immunotherapy. PubMedPubMedCentral
Puzanov I, Diab A, Abdallah K, Bingham CO 3rd, Brogdon C, Dadu R, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) toxicity management working group. J Immunother Cancer. 2017;5:95. https://doi.org/10.1186/s40425-017-0300-z. PubMedPubMedCentral
Hoos A. Development of immune-oncology drugs—from CTLA4 to PD1 to next generations. Nat Rev Drug Discov. 2016;14(4):235–47. https://doi.org/10.1038/nrd.2015.35.
Weber JS, Kahler KC, Hauschild A, et al. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7. PubMed
Haanen J, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;28:iv119–42. https://doi.org/10.1093/annonc/mdx225.
Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow up. Ann Oncol Off J Euro Soc Med Oncol. 2017;28:iv119–iv42.
• Abu-Sbeih H, Ali FS, Luo W, et al. Importance of endoscopic and histologic evaluation in the management of immune checkpoint inhibitor-induced colitis. J Immunother Cancer. 2018;6(1):95. https://doi.org/10.1186/s40425-018-0411-1 This study highlights endoscopic and histologic features of immune-mediated colitis and their association with disease outcomes.
Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48. PubMed
Downey SG, Klapper JA, Smith FO, Yang JC, Sherry RM, Royal RE, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13:6681–8. https://doi.org/10.1158/1078-0432.CCR-07-0187. PubMedPubMedCentral
Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785–92. PubMed
Haratani K, Hayashi H, Chiba Y, Kudo K, Yonesaka K, Kato R, et al. Association of immune related adverse events over a period of 6 weeks is associated with nivolumab efficacy in patients with non-small cell lung cancer. JAMA Oncol. 2018;4(3):374–8. https://doi.org/10.1001/jamaoncol.2017.2925. PubMed
Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resectable and unresectable metastatic melanoma: characteristics of immune related adverse events and associate with outcomes. Clin Cancer Res. 2016;22(4):886–94. https://doi.org/10.1158/1078-0432.CCR-15-1136. PubMed
Sarnaik AA, Yu B, Yu D, et al. Extended dose ipilimumab with a peptide vaccine: immune correlates associated with clinical benefit in patients with resected high-risk stage IIIC/IV melanoma. Clin Can Res An Off J Am Associ Cancer Rese. 2011;17:896–906.
Horvat TZ, Adel NG, Dang T-O, Momtaz P, Postow MA, Callahan MK, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33:3193–8. https://doi.org/10.1200/JCO.2015.60.8448. PubMedPubMedCentral
Weinstock C, Skhozin S, Suzman D, et al. United States Food and Drug Administration approval summary: atezolizumab for metastatic non-small cell lyng cancer. Clin Cancer Res. 2017;23(16):4534–45. PubMed
Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh A, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicenter, randomized, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700–12. PubMedPubMedCentral
• Marthey L, Mateus C, Mussini C, Nachury M, Nancey S, Grange F, et al. Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J Crohns Colitis. 2016;10:395–401. https://doi.org/10.1093/ecco-jcc/jjv227 This study describes CTLA-4-induced enterocolitis and describes similarities between this entity and inflammatory bowel disease and that management should be similar. PubMed
Herbst RS, Baas P, Kim D. Pembrolizumab versus docetaxel for previously treated PD-L1 positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet. 2016;387:1540–50. https://doi.org/10.1016/S0140-6736(15)01281-7. PubMed
Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044–51. https://doi.org/10.1158/1078-0432.CCR-07-4079. PubMed
Ibrahim RA, Berman DM, DePril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol. 2011;29(15_suppl):8583.
Wang DY, Ye F, Zhao S, Johnson DB. Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis. Oncoimmunology. 2017;6(10):e1344805. https://doi.org/10.1080/2162402X.2017.1344805. PubMedPubMedCentral
Dougan M. Checkpoint blockade toxicity and immune homeostasis in the gastrointestinal tract. Front Immunol. 2017. https://doi.org/10.3389/fimmu.2017.01547.
Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patient s with pretreated advanced melanoma: a randomized, double-blind, multicenter phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64. PubMed
Robert C, Schacter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32. PubMed
Menzies AM, Johnson DB, Ramanujam S, Atkinson VG, Wong ANM, Park JJ, et al. Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab. Ann Oncol. 2017;28:368–76. PubMed
Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2(2):234–40. https://doi.org/10.1001/jamaoncol.2015.4368. PubMed
Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott D, et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2016;17:1558–68. PubMedPubMedCentral
Danlos FX, Pagès C, Roux J, et al. Atypical severe immune-related adverse effects resulting from sequenced immunotherapy in melanoma. Melanoma Res. 2015;25:178–9. PubMed
Khoja L, Butler MO, Chappell MA, et al. Increased treatment-related toxicity subsequent to an anti-PD-1 agent. Curr Oncol. 2015;22(4):320–2.
Lord JD, Hackman RC, Moklebust A, et al. Refractory colitis following anti-CTLA4 antibody therapy: analysis of mucosal FOXP3+ T cells. Dig Dis Sci. 2010;55:1396–405. PubMed
Gentile NM, D’Souza A, Fujii LL, Wu TT, Murray JA. Association between ipilimumab and celiac disease. Mayo Clin Proc. 2013;88:414–7. https://doi.org/10.1016/j.mayocp.2013.01.015. PubMed
Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One. 2016;11:e0160221. https://doi.org/10.1371/journal.pone.0160221.s004. PubMedPubMedCentral
Kobayashi M, Yamaguchi O, Nagata K, Nonaka K, Ryozawa S. Acute hemorrhagic gastritis after nivolumab treatment. Gastrointest Endosc. 2017;86(5):915–6. https://doi.org/10.1016/j.gie.2017.04.033. PubMed
Verschuren EC, van den Eertwegh AJ, Wonders J, Slangen RM, van Delft F, van Bodegraven A, et al. Clinical, endoscopic, and histologic characteristics of ipilimumab-associated colitis. Clin Gastroenterol Hepatol. 2016;14:836–42. PubMed
• Abu-Sbeih H, Ali FS, Alsaadi D, et al. Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study. J Immunother Cancer. 2018;6:142 This study demonstrates that vedolizumab can be a viable alternative to infliximab in the treatment of certain patients with immune-mediated colitis.
Abej E, El-Matary W, Singh H, Bernstein CN. The utility of fecal calprotectin in the real-world clinical care of patients with inflammatory bowel disease. Canadian J Gastroenterol Hepatol. 2016: 6 pages:2483261.
Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review. JAMA Oncol. 2016;2:1346–53. https://doi.org/10.1001/jamaoncol.2016.1051. PubMed
• Abu-Sbeih H, Ali FS, Wang X, et al. Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis. J Immunother Cancer. 2019;7:93. https://doi.org/10.1186/s40425-019-0577-1 This study demonstrates that early intervention with biologic therapy improved clinical outcomes in patients with immune-mediated colitis.
Abu-Sbeih H, Tang T, Ali FS, et al. The impact of immune checkpoint inhibitor-related adverse events and their immunosuppressive treatment of patients outcomes. J Immunother Precis Oncol. 2018;1:7–18.
•• Clinical management algorithms - the University of Texas MD Anderson Cancer Center. Evaluation and management of suspected immune-mediated colitis/ diarrhea. https://www.Mdanderson.Org/content/dam/mdanderson/documents/for-physicians/algorithms/clinical-management/clinmanagement-immune-mediated-colitis-web-algorithm.Pdf. 2018. These guidelines provide step-by-step management for patients with immune-mediated colitis.
Hseih AH, Ferman M, Brown MP, et al. Vedolizumab: a novel treatment for ipilimumab-induced colitis. BMJ Case Rep. 2016. https://doi.org/10.1136/bcr-2016-216641.
Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D'Haens G, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2017;66:839–51. PubMed
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-pd-1 immunotherapy in melanoma patients. Science. 2018;359:97–103. PubMed
Chaput N, Lepage P, Coutzac C, Soularue E, le Roux K, Monot C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28:1368–79. PubMed
Schadendorf D, Wolchok JD, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;34:3807–14. https://doi.org/10.1200/JCO.2017.73.2289.
Amin A, de Pril V, Hamid O, et al. Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity. J Clin Oncol. 2009;27(15_suppl):9037–7.
Baurain JF, Smylie M, Ascierto PA, et al. Outcomes of ipilimumab treatment-related adverse events in patients with metastatic melanoma (MM) who received systemic corticosteroids in a phase 3 trial. J Clin Oncol. 2012;30(15_suppl):8539–9. https://doi.org/10.1200/jco.2012.30.15_suppl.8539.
U.S. Department of Health and Human Services. National Institutes of Health. National Cancer Institute. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf . Accessed 1 April 2019.
•• Thompson JA. New NCCN guidelines: recognition and management of immunotherapy-related toxicity. J Natl Compr Cancer Netw. 2018;15:594–6 These are the current National Comprehensive Cancer Network guidelines on management of immune-related adverse events. PubMed
- Immune-Mediated Colitis
MD Tara Menon
MD, MPH, FACG Anita Afzali
- Springer US
Current Treatment Options in Gastroenterology
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