Immunotherapy-induced Colitis

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a variety of malignancies including advanced melanoma, non–small cell lung cancer, renal cell carcinoma, head and neck cancers among others. Since their introduction, there has been significant improvement in survival and prognosis in patients with advanced malignancies. Unfortunately, improved outcomes have come at a price of significant immune-related adverse events, with those of the gastrointestinal tract being the most common. Gastrointestinal immune-related adverse events frequently present as diarrhea and colitis, the severity of which can range from mild diarrhea to fulminant colitis with intestinal perforation. Currently, management of ICI-induced colitis is primarily guided by retrospective studies and expert opinion. A significant number of ICI-induced colitis responds to high-dose corticosteroids; however, some patients require further therapy with biologics. There is limited information on the factors which may predispose patients to ICI-induced colitis. Future research elucidating these risk factors along with development of a scoring system could allow for risk-stratification of patients before initiation of ICI therapy. Such a system may help clinicians and patients keep a high index of suspicion regarding ICI-induced colitis and could hopefully reduce the incidence of severe cases. Similarly, future studies should investigate protective factors against ICI-induced colitis, which could potentially allow more patients to safely benefit from ICI therapy.

[1]  S. Peters,et al.  Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. , 2022, Annals of oncology : official journal of the European Society for Medical Oncology.

[2]  Douglas B. Johnson,et al.  Immune-checkpoint inhibitors: long-term implications of toxicity , 2022, Nature Reviews Clinical Oncology.

[3]  E. Mansoor,et al.  Immune Checkpoint Inhibitor Induced Colitis: A Nationwide Population-Based Study. , 2021, Clinics and research in hepatology and gastroenterology.

[4]  P. Kienle,et al.  Checkpoint Inhibitor-Induced Colitis—A Clinical Overview of Incidence, Prognostic Implications and Extension of Current Treatment Options , 2021, Pharmaceuticals.

[5]  M. Tewari,et al.  Targeting the Gut Microbiome to Mitigate Immunotherapy-Induced Colitis in Cancer. , 2021, Trends in cancer.

[6]  Xubao Liu,et al.  Immunotherapy-Associated Pancreatic Adverse Events: Current Understanding of Their Mechanism, Diagnosis, and Management , 2021, Frontiers in Oncology.

[7]  K. Blenman,et al.  Checkpoint Inhibitor Colitis Shows Drug-Specific Differences in Immune Cell Reaction That Overlap With Inflammatory Bowel Disease and Predict Response to Colitis Therapy. , 2021, American journal of clinical pathology.

[8]  J. Chaim,et al.  A phase II trial of durvalumab and tremelimumab in metastatic, non‐urothelial carcinoma of the urinary tract , 2020, Cancer medicine.

[9]  K. Nan,et al.  The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors , 2020, Journal of experimental & clinical cancer research : CR.

[10]  R. Scolyer,et al.  Clinicopathological characteristics and management of colitis with anti-PD1 immunotherapy alone or in combination with ipilimumab , 2020, Journal for ImmunoTherapy of Cancer.

[11]  A. Rubio‐Tapia,et al.  AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor (ICI) Colitis and Hepatitis: Expert Review. , 2020, Gastroenterology.

[12]  Jun Wang,et al.  Predictive Biomarkers of Immune Checkpoint Inhibitors-Related Toxicities , 2020, Frontiers in Immunology.

[13]  A. Kambadakone,et al.  Diagnostic utility of CT for suspected immune checkpoint inhibitor enterocolitis , 2020, Journal for ImmunoTherapy of Cancer.

[14]  O. Brain,et al.  Immunotherapy induced enterocolitis and gastritis - What to do and when? , 2020, Best practice & research. Clinical gastroenterology.

[15]  M. Galsky,et al.  Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial. , 2020, Cancer cell.

[16]  M. Suarez‐Almazor,et al.  Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors , 2020, Supportive Care in Cancer.

[17]  Manyu Li,et al.  Differential risks of immune-related colitis among various immune checkpoint inhibitor regimens. , 2020, International immunopharmacology.

[18]  H. Ogata,et al.  Clinical, Endoscopic, and Pathological Characteristics of Immune Checkpoint Inhibitor-Induced Gastroenterocolitis , 2020, Digestive Diseases and Sciences.

[19]  J. Larkin,et al.  British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis. , 2020, The lancet. Gastroenterology & hepatology.

[20]  Hannah L Williams,et al.  Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy , 2020, Cell.

[21]  Z. Gong,et al.  Immune Checkpoint Inhibitor-Mediated Diarrhea and Colitis: A Clinical Review. , 2020, JCO oncology practice.

[22]  A. Giobbie-Hurder,et al.  Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor‐induced colitis , 2020, Cancer.

[23]  H. Dupont,et al.  Fecal microbiota transplantation (FMT) for immune checkpoint inhibitor induced–colitis (IMC) refractory to immunosuppressive therapy. , 2020 .

[24]  P. Klenerman,et al.  Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way? , 2020, British Journal of Cancer.

[25]  Douglas B. Johnson,et al.  Demographic Factors Associated with Toxicity in Patients Treated with Anti–Programmed Cell Death-1 Therapy , 2020, Cancer Immunology Research.

[26]  Xuchen Zhang,et al.  Pathologic Manifestations of Gastrointestinal and Hepatobiliary Injury in Immune Checkpoint Inhibitor Therapy. , 2020, Archives of pathology & laboratory medicine.

[27]  P. Boland,et al.  Use of Fecal Microbial Transplantation for Immune Checkpoint Inhibitor Colitis , 2020, ACG case reports journal.

[28]  K. Reynolds,et al.  Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls , 2020, Current Oncology Reports.

[29]  M. Dougan Gastrointestinal and Hepatic Complications of Immunotherapy: Current Management and Future Perspectives , 2020, Current Gastroenterology Reports.

[30]  Hamzah Abu-Sbeih,et al.  Gut Microbiome and Immune Checkpoint Inhibitor-Induced Enterocolitis , 2020, Digestive Diseases and Sciences.

[31]  S. Hanauer,et al.  Checkpoint Inhibitor-Induced Colitis. , 2020, The American journal of gastroenterology.

[32]  Hamzah Abu-Sbeih,et al.  Immune-checkpoint inhibitors induced diarrhea and colitis: a review of incidence, pathogenesis and management. , 2020, Current opinion in gastroenterology.

[33]  Douglas B. Johnson,et al.  Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  F. Farraye,et al.  "Immune checkpoint inhibitor-related luminal GI adverse events". , 2019, Gastrointestinal endoscopy.

[35]  S. Tirumani,et al.  Imaging and clinical manifestations of immune checkpoint inhibitor-related colitis in cancer patients treated with monotherapy or combination therapy , 2019, Abdominal Radiology.

[36]  R. Sullivan,et al.  Budesonide treatment for microscopic colitis from immune checkpoint inhibitors , 2019, Journal of Immunotherapy for Cancer.

[37]  H. Iijima,et al.  Immune checkpoint inhibitor-induced diarrhea/colitis: Endoscopic and pathologic findings , 2019, World journal of gastrointestinal pathophysiology.

[38]  J. Marshall,et al.  Workup and Management of Immune-Mediated Colitis in Patients Treated with Immune Checkpoint Inhibitors. , 2019, The oncologist.

[39]  G. Coukos,et al.  Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance , 2019, Nature Reviews Clinical Oncology.

[40]  R. Bell,et al.  Delayed immune-related events (DIRE) after discontinuation of immunotherapy: diagnostic hazard of autoimmunity at a distance , 2019, Journal of Immunotherapy for Cancer.

[41]  Jianjun Gao,et al.  Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  P. Grivas,et al.  Preexisting Autoimmune Disease: Implications for Immune Checkpoint Inhibitor Therapy in Solid Tumors. , 2019, Journal of the National Comprehensive Cancer Network : JNCCN.

[43]  Amitabh Srivastava,et al.  Lymphocytic colitis–like pattern of mucosal injury and the challenges in diagnosing cancer immunotherapy‐related toxicity , 2019, Cancer.

[44]  Subrata Ghosh,et al.  The Role of Vitamin D in Inflammatory Bowel Disease: Mechanism to Management , 2019, Nutrients.

[45]  A. Jazaeri,et al.  Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor–induced colitis , 2019, Journal of Immunotherapy for Cancer.

[46]  I. Kohane,et al.  Pre-existing autoimmune disease and the risk of immune-related adverse events among patients receiving checkpoint inhibitors for cancer , 2019, Cancer Immunology, Immunotherapy.

[47]  N. Malhotra,et al.  Immune checkpoint inhibitor-induced colitis: A comprehensive review , 2019, World journal of clinical cases.

[48]  Y. Zhou,et al.  Efficacy and safety of CTLA‐4 inhibitors combined with PD‐1 inhibitors or chemotherapy in patients with advanced melanoma , 2019, International immunopharmacology.

[49]  O. Ahmad,et al.  Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management , 2019, Therapeutic advances in gastroenterology.

[50]  D. Bomze,et al.  Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors. , 2019, European journal of cancer.

[51]  Alberto Martin,et al.  Impact of the gut microbiota on immune checkpoint inhibitor-associated toxicities , 2019, Therapeutic advances in gastroenterology.

[52]  A. Araújo,et al.  Management of Gastrointestinal Toxicity from Immune Checkpoint Inhibitor , 2018, GE - Portuguese Journal of Gastroenterology.

[53]  R. Sullivan,et al.  Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis , 2018, JAMA oncology.

[54]  A. Charabaty,et al.  Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor–induced colitis: a multi-center study , 2018, Journal of Immunotherapy for Cancer.

[55]  B. Helmink,et al.  Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis , 2018, Nature Medicine.

[56]  J. Sosman,et al.  Immune Checkpoint Inhibitor Toxicity in 2018 , 2018, JAMA.

[57]  G. Raju,et al.  Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis , 2018, Journal of Immunotherapy for Cancer.

[58]  Jianjun Gao,et al.  Can Immune Checkpoint Inhibitors Induce Microscopic Colitis or a Brand New Entity? , 2018, Inflammatory bowel diseases.

[59]  Mina Sarofim,et al.  Rare case of delayed onset colitis due to immunotherapy for malignant melanoma , 2018, ANZ journal of surgery.

[60]  M. Carlino,et al.  Immune Checkpoint Inhibitor Toxicity , 2018, Current Oncology Reports.

[61]  R. Bresalier,et al.  Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. , 2018, Inflammatory bowel diseases.

[62]  M. Burton,et al.  Immunotherapy-Induced Colitis: An Emerging Problem for the Hospitalist , 2018, Journal of hospital medicine.

[63]  T. Pawlik,et al.  Histopathological and immunophenotypic features of ipilimumab‐associated colitis compared to ulcerative colitis , 2018, Journal of internal medicine.

[64]  Y. Huang,et al.  Anti-Inflammatory Biologics and Anti-Tumoral Immune Therapies-Associated Colitis: A Focused Review of Literature , 2018, Gastroenterology research.

[65]  O. Rahma,et al.  Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management. , 2018, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[66]  D. Karamchandani,et al.  Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists’ perspective , 2018, Journal of Clinical Pathology.

[67]  S. Laurie,et al.  The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis , 2018, Journal of immunotherapy.

[68]  C. McNeil,et al.  Isolated immune-related pancreatic exocrine insufficiency associated with pembrolizumab therapy. , 2018, Immunotherapy.

[69]  M. Suarez‐Almazor,et al.  Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  E. Rozeman,et al.  Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management , 2018, ESMO Open.

[71]  M. Suarez‐Almazor,et al.  Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group , 2017, Journal of Immunotherapy for Cancer.

[72]  E. Montgomery,et al.  Immune checkpoint inhibitor colitis: the flip side of the wonder drugs , 2017, Virchows Archiv.

[73]  M. Dougan Checkpoint Blockade Toxicity and Immune Homeostasis in the Gastrointestinal Tract , 2017, Front. Immunol..

[74]  D. Planchard,et al.  Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities , 2017, Journal of Crohn's & colitis.

[75]  L. Siu,et al.  Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[76]  Douglas B. Johnson,et al.  Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: A systematic review and meta-analysis , 2017, Oncoimmunology.

[77]  N. Reinmuth,et al.  Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. , 2017, Cancer treatment reviews.

[78]  A. Tfayli,et al.  Late-Onset Inflammatory Bowel Disease-Like Syndrome after Ipilimumab Therapy: A Case Report , 2017, Case Reports in Oncology.

[79]  G. Lauwers,et al.  Histopathologic Features of Colitis Due to Immunotherapy With Anti-PD-1 Antibodies , 2017, The American journal of surgical pathology.

[80]  D. Schadendorf,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. , 2017, The Lancet. Oncology.

[81]  F. Hodi,et al.  Diagnostic Comparison of CT Scans and Colonoscopy for Immune-Related Colitis in Ipilimumab-Treated Advanced Melanoma Patients , 2017, Cancer Immunology Research.

[82]  M. Grimm,et al.  Nebenwirkungen der Immun-Checkpoint-Inhibitoren , 2017, Der Urologe.

[83]  A. Carneiro,et al.  Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis , 2017, Cancer Immunology, Immunotherapy.

[84]  M. Postow,et al.  Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. , 2016, JAMA oncology.

[85]  R. Sullivan,et al.  Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[86]  J. Wolchok,et al.  corrigenda to Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies [Ann Oncol 26 (2015) 2375-2391, doi: 10.1093/annonc/mdv383] , 2016 .

[87]  M. Bissonnette,et al.  Immune--Mediated Colitis with Novel Immunotherapy : PD-1 Inhibitor Associated Gastrointestinal Toxicity. , 2016, Acta gastro-enterologica Belgica.

[88]  A. V. van Bodegraven,et al.  Clinical, Endoscopic, and Histologic Characteristics of Ipilimumab-Associated Colitis. , 2016, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[89]  M. Gariboldi,et al.  Comment on ‘Circulating cell-free miRNAs as biomarker for triple-negative breast cancer'—Methodological challenges in combining miRNAs as circulating biomarkers , 2016, British Journal of Cancer.

[90]  D. Planchard,et al.  Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease. , 2016, Journal of Crohn's & colitis.

[91]  J. Larkin,et al.  Management of toxicities of immune checkpoint inhibitors. , 2016, Cancer treatment reviews.

[92]  C. Huttenhower,et al.  Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis , 2016, Nature Communications.

[93]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

[94]  M. Valsecchi Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. , 2015, The New England journal of medicine.

[95]  J. Kirkwood,et al.  Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma , 2015, Journal of Immunotherapy for Cancer.

[96]  P. Lorigan,et al.  Optimal management of immune-related toxicities associated with checkpoint inhibitors in lung cancer. , 2015, Lung cancer.

[97]  Elizabeth R. Paine,et al.  Colonoscopic evaluation in ulcerative colitis , 2014, Gastroenterology report.

[98]  I. Puzanov,et al.  Infectious Colitis Associated With Ipilimumab Therapy , 2014, Gastroenterology research.

[99]  D. Altman,et al.  Reliability and initial validation of the ulcerative colitis endoscopic index of severity. , 2013, Gastroenterology.

[100]  A. Tarhini Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management , 2013, Scientifica.

[101]  L. Zitvogel,et al.  Targeting PD-1/PD-L1 interactions for cancer immunotherapy , 2012, Oncoimmunology.

[102]  A. Hauschild,et al.  Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. , 2010, Seminars in oncology.

[103]  J. Barkin,et al.  Cytotoxic T-Lymphocyte-Associated Antigen 4 Antibody-Induced Colitis and Its Management with Infliximab , 2009, Digestive Diseases and Sciences.

[104]  J. Bluestone,et al.  Interactions between programmed death-1 and programmed death ligand-1 promote tolerance by blocking the T cell receptor-induced stop signal , 2009, Nature Immunology.

[105]  A. Maraveyas,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 , 2009, Clinical Cancer Research.

[106]  J. Allison,et al.  The B7 Family and Cancer Therapy: Costimulation and Coinhibition , 2007, Clinical Cancer Research.

[107]  A. Feldman,et al.  Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[108]  W. Tremaine,et al.  Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. , 1987, The New England journal of medicine.

[109]  B. Scott,et al.  Rectal mucosal plasma cells in inflammatory bowel disease. , 1983, Gut.

[110]  Hamzah Abu-Sbeih,et al.  Gastrointestinal Tract Adverse Events. , 2020, Advances in experimental medicine and biology.

[111]  B. Říhová,et al.  [History of Immuno-therapy -  from Coley Toxins to Check-points of the Immune Reaction]. , 2015, Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti.

[112]  S. Targan,et al.  Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. , 2010, Cancer immunity.

[113]  D. Schadendorf,et al.  Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. , 2010, Cancer immunity.

[114]  M. Gordon Enterocolitis in Patients With Cancer After Antibody Blockade of Cytotoxic T-Lymphocyte–Associated Antigen 4 , 2008 .

[115]  S. Rosenberg,et al.  Risk of bowel perforation in patients receiving interleukin-2 after therapy with anti-CTLA 4 monoclonal antibody. , 2007, Journal of immunotherapy.