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  • Review Article
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Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management

Nature Reviews Gastroenterology & Hepatology volume 15, pages 222–234 (2018)Cite this article

Subjects

Key Points

  • Immune checkpoint inhibitors promote an antitumour immune response by blocking signalling via either the cytotoxic T lymphocyte antigen 4 (CTLA4) pathway or the programmed cell death protein 1 (PD1) pathway

  • Their use can result in immune-related adverse events, including the development of gastrointestinal inflammation, which shares certain clinicopathological features with IBD

  • In suspected cases of persistent mild or moderate-to-severe immune checkpoint inhibitor-induced gastrointestinal inflammation, endoscopic and histological investigation should be arranged to confirm the diagnosis, and other possible causes of symptoms should be excluded

  • Corticosteroids should be used in the first instance to manage inflammation, and in patients who are refractory to corticosteroids, the addition of infliximab or vedolizumab should be considered

Abstract

Immune checkpoint inhibitor therapies are a novel group of monoclonal antibodies with proven effectiveness in a wide range of malignancies, including melanoma, renal cell carcinoma, non-small-cell lung cancer, urothelial carcinoma and Hodgkin lymphoma. Their use in a range of other indications, such as gastrointestinal and head and neck cancer, is currently under investigation. The number of agents included in this drug group is increasing, as is their use. Although they have the potential to improve the treatment of advanced malignancies, they are also associated with a substantial risk of immune-related adverse events. The incidence of gastrointestinal toxicity associated with their use is second only in frequency to dermatological toxicity. Thus, gastroenterologists can expect to be increasingly frequently consulted by oncologists as part of a multidisciplinary approach to managing toxicity. Here, we describe this novel group of agents and their mechanisms of action. We review the manifestations of gastrointestinal toxicity associated with their use so that it can be recognized early and diagnosed accurately. We also discuss the proposed mechanisms underlying this toxicity and describe an algorithmic and, wherever possible, evidence-based approach to its management.

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Figure 1: The role of CTLA4 and PD1 in T cell activation.
Figure 2: Gastrointestinal toxicity observed among selected randomized controlled trials of immune checkpoint inhibitor agents.
Figure 3: Suggested algorithm for the management of immune checkpoint inhibitor-associated gastrointestinal toxicity.

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References

  1. Adachi, K. & Tamada, K. Immune checkpoint blockade opens an avenue of cancer immunotherapy with a potent clinical efficacy. Cancer Sci. 106, 945–950 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Villadolid, J. & Amin, A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. 4, 560–575 (2015). This is a comprehensive and clinically useful review of irAEs, which are classified by organ system.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012). This is an in-depth Review of checkpoint inhibitors as a potent anticancer treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lafferty, K. J. & Cunningham, A. J. A new analysis of allogeneic interactions. Aust. J. Exp. Biol. Med. Sci. 53, 27–42 (1975).

    Article  CAS  PubMed  Google Scholar 

  5. Gmunder, H. & Lesslauer, W. A. 45-kDa human T-cell membrane glycoprotein functions in the regulation of cell proliferative responses. Eur. J. Biochem. 142, 153–160 (1984).

    Article  CAS  PubMed  Google Scholar 

  6. Azuma, M., Cayabyab, M., Buck, D., Phillips, J. H. & Lanier, L. L. CD28 interaction with B7 costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J. Exp. Med. 175, 353–360 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Schwartz, R. H. A cell culture model for T lymphocyte clonal anergy. Science 248, 1349–1356 (1990).

    Article  CAS  PubMed  Google Scholar 

  8. Brunet, J. F. et al. A new member of the immunoglobulin superfamily — CTLA-4. Nature 328, 267–270 (1987). This is the first research study describing the discovery of CTLA4.

    Article  CAS  PubMed  Google Scholar 

  9. Chen, L. et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell 71, 1093–1102 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Krummel, M. F. & Allison, J. P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Walunas, T. L. et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1, 405–413 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Walunas, T. L., Bakker, C. Y. & Bluestone, J. A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med. 183, 2541–2550 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Linsley, P. S. et al. CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 174, 561–569 (1991).

    Article  CAS  PubMed  Google Scholar 

  14. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008). This study identifies the key role CTLA4 has in T reg cell function and homeostasis.

    Article  CAS  PubMed  Google Scholar 

  17. Zheng, Y. et al. Acquisition of suppressive function by activated human CD4+ CD25- T cells is associated with the expression of CTLA-4 not FoxP3. J. Immunol. 181, 1683–1691 (2008).

    Article  CAS  PubMed  Google Scholar 

  18. Fallarino, F. et al. CD40 ligand and CTLA-4 are reciprocally regulated in the Th1 cell proliferative response sustained by CD8(+) dendritic cells. J. Immunol. 169, 1182–1188 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Sage, P. T., Paterson, A. M., Lovitch, S. B. & Sharpe, A. H. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41, 1026–1039 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang, C. J. et al. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proc. Natl Acad. Sci. USA 112, 524–529 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Zhang, X. et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity 20, 337–347 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Chang, W. S. et al. Cutting edge: Programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J. Immunol. 181, 6707–6710 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Liu, J. et al. Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses. Proc. Natl Acad. Sci. USA 112, 6682–6687 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Petrovas, C. et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203, 2281–2292 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Seillet, C. et al. Deciphering the innate lymphoid cell transcriptional program. Cell Rep. 17, 436–447 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Yu, Y. et al. Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its development pathway. Nature 539, 102–106 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Nishimura, H. & Honjo, T. PD-1: an inhibitory immunoreceptor involved in peripheral tolerance. Trends Immunol. 22, 265–268 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Terawaki, S. et al. IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J. Immunol. 186, 2772–2779 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Nurieva, R. et al. T-Cell tolerance or function is determined by combinatorial costimulatory signals. The EMBO journal 25, 2623–2633 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6, 6692 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Patsoukis, N. et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci. Signal. 5, ra46 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Patsoukis, N., Li, L., Sari, D., Petkova, V. & Boussiotis, V. A. PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. Mol. Cell. Biol. 33, 3091–3098 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Taylor, S. et al. PD-1 regulates KLRG1+ group 2 innate lymphoid cells. J. Exp. Med. 214, 1663–1678 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Goldberg, R., Prescott, N., Lord, G. M., MacDonald, T. T. & Powell, N. The unusual suspects — innate lymphoid cells as novel therapeutic targets in IBD. Nat. Rev. Gastroenterol. Hepatol. 12, 271–283 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Tivol, E. A. et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3, 541–547 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Schubert, D. et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 20, 1410–1416 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bennett, C. L. & Ochs, H. D. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr. Opin. Pediatr. 13, 533–538 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Read, S., Malmstrom, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nature Genet. 47, 979–986 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Anderson, A. C., Joller, N. & Kuchroo, V. K. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44, 989–1004 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Berman, D. et al. The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: the Bristol-Myers Squibb experience. Pharmacol. Ther. 148, 132–153 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00527735 (2012).

  44. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01524991 (2017).

  45. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT00323882 (2014).

  46. Kim, B. J., Jang, H. J., Kim, H. S. & Kim, J. H. Current Status of Immune Checkpoint Inhibitors in Gastrointestinal Cancers. J. Cancer 8, 1460–1465 (2017). This is an up to date review of the potential role of immune checkpoint inhibitors in gastrointestinal cancers, which is of particular interest to gastroenterologists and hepatologists.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Motzer, R. J. et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J. Clin. Oncol. 33, 1430–1437 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Younes, A. et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 17, 1283–1294 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389, 2492–2502 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Rosenberg, J. E. et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387, 1909–1920 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bristol-Myers Squibb. Ipilimumab U. S. prescribing information: Risk evaluation and mitigation strategy. U.S. Food & Drug Administration https://www.fda.gov/downloads/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm249435.pdf (2012).

  56. Fecher, L. A., Agarwala, S. S., Hodi, F. S. & Weber, J. S. Ipilimumab and its toxicities: a multidisciplinary approach. Oncology 18, 733–743 (2013). This article details the importance of collaborative multidisciplinary care for the optimal recognition and management of irAEs.

    Article  CAS  Google Scholar 

  57. Weber, J. S., Kahler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. O'Day, S. J. et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann. Oncol. 21, 1712–1717 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Wolchok, J. D. et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 11, 155–164 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Blansfield, J. A. et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J. Immunother. 28, 593–598 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Byun, D. J., Wolchok, J. D., Rosenberg, L. M. & Girotra, M. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat. Rev. Endocrinol. 13, 195–207 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dillard, T., Yedinak, C. G., Alumkal, J. & Fleseriu, M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary 13, 29–38 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Bertrand, A., Kostine, M., Barnetche, T., Truchetet, M. E. & Schaeverbeke, T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 13, 211 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Yang, J. C. et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. 30, 825–830 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Downey, S. G. et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clinical cancer research: an official journal of the American Association for Cancer Res. 13, 6681–6688 (2007).

    CAS  Google Scholar 

  66. Beck, K. E. et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J. Clin. Oncol. 24, 2283–2289 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Attia, P. et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol. 23, 6043–6053 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Weber, J. S. et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 16, 375–384 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Abdel-Rahman, O. & Fouad, M. Risk of pneumonitis in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Ther. Adv. Respir. Dis. 10, 183–193 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. National Cancer Institute. Common terminology criteria for adverse events (CTCAE) v4.0. European Organization for Research and Treatment of Cancer https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (2009).

  75. Basch, E. The missing voice of patients in drug-safety reporting. N. Engl. J. Med. 362, 865–869 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fromme, E. K., Eilers, K. M., Mori, M., Hsieh, Y. C. & Beer, T. M. How accurate is clinician reporting of chemotherapy adverse effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 22, 3485–3490 (2004).

    Article  Google Scholar 

  77. Pakhomov, S. V., Jacobsen, S. J., Chute, C. G. & Roger, V. L. Agreement between patient-reported symptoms and their documentation in the medical record. Am. J. Managed Care 14, 530–539 (2008).

    Google Scholar 

  78. Atkinson, T. M. et al. Reliability of adverse symptom event reporting by clinicians. Qual. Life Res. 21, 1159–1164 (2012).

    Article  PubMed  Google Scholar 

  79. Basch, E. et al. Adverse symptom event reporting by patients versus clinicians: relationships with clinical outcomes. J. Natl Cancer Institute 101, 1624–1632 (2009).

    Article  Google Scholar 

  80. Quinten, C. et al. Patient self-reports of symptoms and clinician ratings as predictors of overall cancer survival. J. Natl Cancer Institute 103, 1851–1858 (2011).

    Article  Google Scholar 

  81. [No authors listed.] Guidance for industry. Patient-reported outcomes measures: use in medical product development to support labeling claims. U.S. Food & Drug Administration http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282 (2009).

  82. Committee for Medicinal Products for Human Use (CHMP). Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal products. European Medicines Agency http://www.ispor.org/workpaper/emea-hrql-guidance.pdf (2006).

  83. Basch, E. et al. Development of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). J. Natl Cancer Institute 106, dju244 (2014).

    Article  Google Scholar 

  84. Arnold, B. et al. Linguistic validation of the Spanish version of the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Support. Care Cancer 24, 2843–2851 (2016).

    PubMed  Google Scholar 

  85. Baeksted, C. et al. Danish translation and linguistic validation of the U. S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). J. Pain Symptom Manage. 52, 292–297 (2016).

    Article  PubMed  Google Scholar 

  86. Hay, J. L. et al. Cognitive interviewing of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Qual. Life Res. 23, 257–269 (2014).

    Article  PubMed  Google Scholar 

  87. Kirsch, M. et al. Linguistic and content validation of a German-language PRO-CTCAE-based patient-reported outcomes instrument to evaluate the late effect symptom experience after allogeneic hematopoietic stem cell transplantation. Eur. J. Oncol. Nurs. 19, 66–74 (2015).

    Article  PubMed  Google Scholar 

  88. Bennett, A. V. et al. Mode equivalence and acceptability of tablet computer-, interactive voice response system-, and paper-based administration of the U. S. National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Health Qual. Life Outcomes 14, 24 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Dueck, A. C. et al. Validity and Reliability of the US National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). JAMA Oncol. 1, 1051–1059 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Hagelstein, V., Ortland, I., Wilmer, A., Mitchell, S. A. & Jaehde, U. Validation of the German patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE). Ann. Oncol. 27, 2294–2299 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mendoza, T. R. et al. Evaluation of different recall periods for the US National Cancer Institute's PRO-CTCAE. Clin. Trials 14, 255–263 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Abdel-Rahman, O., ElHalawani, H. & Fouad, M. Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Immunotherapy 7, 1213–1227 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Ascierto, P. A. et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 18, 611–622 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Jain, A., Lipson, E. J., Sharfman, W. H., Brant, S. R. & Lazarev, M. G. Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis. World J. Gastroenterol. 23, 2023–2028 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Marthey, L. et al. Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease. J. Crohn's Colitis 10, 395–401 (2016).

    Article  CAS  Google Scholar 

  97. Mary, J. Y. & Modigliani, R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Gut 30, 983–989 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Landi, B. et al. Endoscopic monitoring of Crohn's disease treatment: a prospective, randomized clinical trial. Gastroenterology 102, 1647–1653 (1992).

    Article  CAS  PubMed  Google Scholar 

  99. Jones, J. et al. Relationships between disease activity and serum and fecal biomarkers in patients with Crohn's disease. Clin. Gastroenterol. Hepatol. 6, 1218–1224 (2008).

    Article  PubMed  Google Scholar 

  100. Modigliani, R. et al. Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Gastroenterology 98, 811–818 (1990).

    Article  CAS  PubMed  Google Scholar 

  101. Peyrin-Biroulet, L. et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target. Am. J. Gastroenterol. 110, 1324–1338 (2015).

    Article  CAS  PubMed  Google Scholar 

  102. Baroudjian, B. et al. Anti-PD1-induced collagenous colitis in a melanoma patient. Melanoma Res. 26, 308–311 (2016).

    Article  CAS  PubMed  Google Scholar 

  103. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Article  PubMed  Google Scholar 

  104. Rizvi, N. A. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gielisse, E. A. & de Boer, N. K. Ipilimumab in a patient with known Crohn's disease: to give or not to give? J. Crohn's Colitis 8, 1742 (2014).

    Article  Google Scholar 

  106. Fiocchi, C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115, 182–205 (1998).

    Article  CAS  PubMed  Google Scholar 

  107. Bianchini, F., Kaaks, R. & Vainio, H. Overweight, obesity, and cancer risk. Lancet Oncol. 3, 565–574 (2002).

    Article  PubMed  Google Scholar 

  108. Sandler, D. P., Wilcox, A. J. & Everson, R. B. Cumulative effects of lifetime passive smoking on cancer risk. Lancet 1, 312–315 (1985).

    Article  CAS  PubMed  Google Scholar 

  109. Clemente, J. C., Ursell, L. K., Parfrey, L. W. & Knight, R. The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wu, G. D. et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334, 105–108 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Montassier, E. et al. Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment. Pharmacol. Ther. 42, 515–528 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Ungaro, R. et al. Antibiotics associated with increased risk of new-onset Crohn's disease but not ulcerative colitis: a meta-analysis. Am. J. Gastroenterol. 109, 1728–1738 (2014).

    Article  CAS  PubMed  Google Scholar 

  113. Hill, G. R. et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 90, 3204–3213 (1997).

    CAS  PubMed  Google Scholar 

  114. Naidu, M. U. et al. Chemotherapy-induced and/or radiation therapy-induced oral mucositis — complicating the treatment of cancer. Neoplasia 6, 423–431 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Hsieh, A. H., Ferman, M., Brown, M. P. & Andrews, J. M. Vedolizumab: a novel treatment for ipilimumab-induced colitis. BMJ Case Rep. https://doi.org/10.1136/bcr-2016-216641 (2016).

  116. Bergqvist, V. et al. Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis. Cancer Immunol. Immunother. 66, 581–592 (2017). This is the first and (at the time of writing) only case series to describe the effectiveness of vedolizumab for treating the enterocolitis induced by immune checkpoint inhibitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Berman, D. et al. Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. Cancer Immun. 10, 11 (2010).

    PubMed  PubMed Central  Google Scholar 

  118. Shahabi, V. 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 Med. 11, 75 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Dubin, K. et al. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat. Commun. 7, 10391 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Marshall, J. C., Christou, N. V. & Meakins, J. L. Small-bowel bacterial overgrowth and systemic immunosuppression in experimental peritonitis. Surgery 104, 404–411 (1988).

    CAS  PubMed  Google Scholar 

  121. Aggarwal, V., Williams, M. D. & Beath, S. V. Gastrointestinal problems in the immunosuppressed patient. Arch. Dis. Child 78, 5–8 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Stacey, R. & Green, J. T. Radiation-induced small bowel disease: latest developments and clinical guidance. Ther. Adv. Chron. Dis. 5, 15–29 (2014).

    Article  Google Scholar 

  123. Andreyev, H. J. et al. Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer. Gut 61, 179–192 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Abdel-Wahab, N., Shah, M. & Suarez-Almazor, M. E. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PloS ONE 11, e0160221 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Gentile, N. M., D'Souza, A., Fujii, L. L., Wu, T. T. & Murray, J. A. Association between ipilimumab and celiac disease. Mayo Clin. Proc. 88, 414–417 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Weber, J. 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. 15, 5591–5598 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Mowat, C. et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 60, 571–607 (2011).

    Article  PubMed  Google Scholar 

  128. Walley, T. & Milson, D. Loperamide related toxic megacolon in Clostridium difficile colitis. Postgrad. Med. J. 66, 582 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Brown, J. W. Toxic megacolon associated with loperamide therapy. JAMA 241, 501–502 (1979).

    Article  CAS  PubMed  Google Scholar 

  130. Khalil, J. et al. Venous thromboembolism in cancer patients: an underestimated major health problem. World J. Surg. Oncol. 13, 204 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Bernstein, C. N., Blanchard, J. F., Houston, D. S. & Wajda, A. The incidence of deep venous thrombosis and pulmonary embolism among patients with inflammatory bowel disease: a population-based cohort study. Thromb. Haemost. 85, 430–434 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Andreyev, J. et al. Guidance on the management of diarrhoea during cancer chemotherapy. Lancet Oncol. 15, e447–460 (2014).

    Article  PubMed  Google Scholar 

  133. Horvat, T. Z. 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. 33, 3193–3198 (2015). This study reports on a moderately large series of patients with colitis induced by immune checkpoint inhibitors who were treated with infliximab, as well as a single patient treated with adalimumab.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. O'Connor, A., Marples, M., Mulatero, C., Hamlin, J. & Ford, A. C. Ipilimumab-induced colitis: experience from a tertiary referral center. Ther. Adv. Gastroenterol. 9, 457–462 (2016).

    Article  CAS  Google Scholar 

  135. Verschuren, E. C. et al. Clinical, endoscopic, and histologic characteristics of ipilimumab-associated colitis. Clin. Gastroenterol. Hepatol. 14, 836–842 (2016).

    Article  PubMed  Google Scholar 

  136. Hillock, N. T., Heard, S., Kichenadasse, G., Hill, C. L. & Andrews, J. Infliximab for ipilimumab-induced colitis: a series of 13 patients. Asia Pac. J. Clin. Oncol. 13, e284–e290 (2017).

    Article  PubMed  Google Scholar 

  137. Lankes, K. et al. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: possible role of CMV-mediated immunopathogenesis. Oncoimmunology 5, e1128611 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Spain, L., Diem, S. & Larkin, J. Management of toxicities of immune checkpoint inhibitors. Cancer Treatment Rev. 44, 51–60 (2016).

    Article  CAS  Google Scholar 

  139. Mitchell, K. A., Kluger, H., Sznol, M. & Hartman, D. J. Ipilimumab-induced perforating colitis. J. Clin. Gastroenterol. 47, 781–785 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. Mark A. Samaan and Polychronis Pavlidis: These authors contributed equally: Mark A. Samaan and Polychronis Pavlidis

Authors and Affiliations

  1. Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, First Floor College House, North Wing, St Thomas' Hospital, Westminster Bridge Road, London, UK

    Mark A. Samaan, Nick Powell & Peter M. Irving

  2. Department of Gastroenterology, King's College Hospital, Denmark Hill, London, Brixton, UK

    Polychronis Pavlidis

  3. School of Immunology and Microbial Sciences, New Hunts House, Guy's Campus, King's College London, London, UK

    Polychronis Pavlidis & Nick Powell

  4. Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, Cancer Centre, Guy's Hospital, Great Maze Pond, London, UK

    Sophie Papa

  5. Division of Cancer Studies, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK

    Sophie Papa

Authors
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Contributions

All authors made substantial contributions to discussion of content and reviewed and/or edited the manuscript before submissions. M.A.S. and P.P. researched the contributing data and wrote the article.

Corresponding author

Correspondence to Peter M. Irving.

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Competing interests

M.A.S. has received advisory fees from Hospira and lecture fees from Falk, Hospira, Janssen, MSD and Takeda. S.P. has received advisory fees from Amgen, MSD and Roche and lectures fees from Bristol–Myers Squibb and MSD. N.P. has received advisory fees from AbbVie, Allergan, Debiopharm International, Ferring and Vifor Pharma and lectures fees from Allergan, Falk, Janssen, Tillotts and Takeda. P.M.I. has received advisory fees from AbbVie, Genentech, Hospira, Janssen, MSD, Pharmacosmos, Samsung Bioepis, VH2, Vifor Pharma, Takeda, Topivert and Warner Chilcott, lecture fees from AbbVie, Falk, Ferring and Warner Chilcott and financial support for research from MSD and Takeda. P.P. declares no competing interests.

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Glossary

Antigen-presenting cells

(APCs). Cells that capture, process and display antigens (such as those from microorganisms, environmental toxins and/or tumour neo-antigens) to lymphocytes; they also express co-stimulatory signals (that is, CD80/CD86 expression), which are necessary for lymphocyte activation (proliferation and effector function).

Tolerance

A state in which the adaptive immune system does not respond to an antigen. During T cell development in the thymus, cells that recognize self-antigens are deleted (central tolerance), a process that contributes to self-tolerance, a homeostatic attribute of the adaptive immune system.

Immune checkpoint inhibitors

Drugs that promote an antitumour immune response by blocking signalling via either the cytotoxic T lymphocyte antigen 4 (CTLA4) pathway or the programmed cell death 1 (PD1) pathway.

Co-stimulatory pathway

The necessary, additional activating signal to T cell receptor (CD3) engagement with antigen, which leads T cells towards proliferation and effector function.

Immunological synapse

The crosstalk interface for immune cells where, for example, the antigen presented by an antigen-presenting cell and its surface CD80 molecule engage a T cell through the T cell receptor and CD28, respectively.

Regulatory T cells

(Treg cells). Regulatory cells, usually defined as CD4+CD25+, that are characterized by the expression of the transcription factor forkhead box protein 3 (FOXP3). Through cytokine production (such as IL-10 and transforming growth factor-β (TGFβ)) and cellular interactions (that is, through cytotoxic T lymphocyte antigen 4 (CTLA4)), they suppress the responses of surrounding activated lymphocytes.

CD4+ T effector cells

T cells that, upon activation by an antigen-presenting cell, produce cytokines and drive inflammation. Activated naive cells turn to memory cells that can mount a response to the same antigen much more quickly.

Hypophysitis

An acute or chronic inflammation of the pituitary gland.

Patient-reported outcomes

(PROs). Health outcomes directly reported by the patients who experience them.

Acute abdomen

A rapid onset of severe symptoms that can indicate potentially life-threatening intra-abdominal pathology that requires urgent surgical intervention.

Small intestinal bacterial overgrowth

The presence of excessive bacteria in the small intestine, frequently implicated as the cause of chronic diarrhoea and malabsorption.

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Samaan, M., Pavlidis, P., Papa, S. et al. Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management. Nat Rev Gastroenterol Hepatol 15, 222–234 (2018). https://doi.org/10.1038/nrgastro.2018.14

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