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Gao YQ, Tan YJ, Fang JY. Roles of the gut microbiota in immune-related adverse events: mechanisms and therapeutic intervention. Nat Rev Clin Oncol 2025:10.1038/s41571-025-01026-w. [PMID: 40369317 DOI: 10.1038/s41571-025-01026-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2025] [Indexed: 05/16/2025]
Abstract
Immune checkpoint inhibitors (ICIs) constitute a major breakthrough in the field of cancer therapy; their use has resulted in improved outcomes across various tumour types. However, ICIs can cause a diverse range of immune-related adverse events (irAEs) that present a considerable challenge to the efficacy and safety of these treatments. The gut microbiota has been demonstrated to have a crucial role in modulating the tumour immune microenvironment and thus influences the effectiveness of ICIs. Accumulating evidence indicates that alterations in the composition and function of the gut microbiota are also associated with an increased risk of irAEs, particularly ICI-induced colitis. Indeed, these changes in the gut microbiota can contribute to the pathogenesis of irAEs. In this Review, we first summarize the current clinical challenges posed by irAEs. We then focus on reported correlations between alterations in the gut microbiota and irAEs, especially ICI-induced colitis, and postulate mechanisms by which these microbial changes influence the occurrence of irAEs. Finally, we highlight the potential value of gut microbial changes as biomarkers for predicting irAEs and discuss gut microbial interventions that might serve as new strategies for the management of irAEs, including faecal microbiota transplantation, probiotic, prebiotic and/or postbiotic supplements, and dietary modulations.
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Affiliation(s)
- Ya-Qi Gao
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong-Jie Tan
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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2
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Dong H, Peng Y, Wang X, Cui H. An updated review on immune checkpoint inhibitor-induced colitis: epidemiology, pathogenesis, treatment strategies, and the role of traditional Chinese medicine. Front Immunol 2025; 16:1551445. [PMID: 40165945 PMCID: PMC11955479 DOI: 10.3389/fimmu.2025.1551445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 02/26/2025] [Indexed: 04/02/2025] Open
Abstract
Immune checkpoint inhibitor-induced colitis (irColitis) is a common and severe adverse reaction to immune checkpoint inhibitors (ICIs), significantly impacting the treatment outcomes and quality of life of cancer patients. Epidemiological studies indicate that the incidence of irColitis is associated with factors such as the type of ICIs, the patient's gender, age, and medical history. Although the exact pathophysiology remains unclear, irColitis is thought to be related to immune system activation and dysregulation, gut microbiota imbalance, and impaired epithelial barrier function. This review summarized the epidemiology, clinical presentation, diagnostic criteria, and pathogenesis of irColitis. Additionally, the standard and novel therapeutic strategies of irColitis, including corticosteroids, biologics, and gut microbiota interventions, more importantly the potential and application of Traditional Chinese Medicine (TCM). Future researches call for deeper mechanistic investigations, the development of biomarkers, and reveal the integration of TCM therapies within individual immunotherapy frameworks.
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Affiliation(s)
- Huijing Dong
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Yanmei Peng
- Department of Oncology, Fangshan Hospital Beijing University of Chinese Medicine, Beijing, China
| | - Xinmeng Wang
- China-Japan Friendship Clinical Medical College, Beijing University of Chinese Medicine, Beijing, China
| | - Huijuan Cui
- Department of Integrative Oncology, China-Japan Friendship Hospital, Beijing, China
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3
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Giesler S, Riemer R, Lowinus T, Zeiser R. Immune-mediated colitis after immune checkpoint inhibitor therapy. Trends Mol Med 2025; 31:265-280. [PMID: 39477757 DOI: 10.1016/j.molmed.2024.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/23/2024] [Accepted: 09/30/2024] [Indexed: 03/15/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.
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Affiliation(s)
- Sophie Giesler
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roxane Riemer
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Theresa Lowinus
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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4
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Shatila M, Wang Y. Response. Gastrointest Endosc 2025; 101:696-698. [PMID: 40024649 DOI: 10.1016/j.gie.2024.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 11/03/2024] [Indexed: 03/04/2025]
Affiliation(s)
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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5
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Colli Cruz C, Moura Nascimento Santos MJ, Wali S, Varatharajalu K, Thomas A, Wang Y. Gastrointestinal toxicities associated with immune checkpoint inhibitors therapy: risks and management. Immunotherapy 2025; 17:293-303. [PMID: 40055892 PMCID: PMC12013428 DOI: 10.1080/1750743x.2025.2473305] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/25/2025] [Indexed: 04/22/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) have greatly improved cancer treatment by boosting the immune system's ability to target tumors. However, they can also cause serious side effects, particularly in the digestive system. These include immune-related diarrhea, inflammation of the intestines and, less commonly, inflammation of the stomach or esophagus. This review underscores the importance of early detection, accurate diagnosis, and timely treatment to improve patient outcomes. It also highlights the need for further research to develop strategies to reduce gastrointestinal toxicities and enhance the overall effectiveness of ICIs in cancer therapy.
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Affiliation(s)
- Carolina Colli Cruz
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Sharada Wali
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Krishnavathana Varatharajalu
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha Thomas
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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6
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Braun LM, Giesler S, Andrieux G, Riemer R, Talvard-Balland N, Duquesne S, Rückert T, Unger S, Kreutmair S, Zwick M, Follo M, Hartmann A, Osswald N, Melchinger W, Chapman S, Hutchinson JA, Haferkamp S, Torster L, Kött J, Gebhardt C, Hellwig D, Karantzelis N, Wallrabenstein T, Lowinus T, Yücel M, Brehm N, Rawluk J, Pfeifer D, Bronsert P, Rogg M, Mattern S, Heikenwälder M, Fusco S, Malek NP, Singer S, Schmitt-Graeff A, Ceteci F, Greten FR, Blazar BR, Boerries M, Köhler N, Duyster J, Ihorst G, Lassmann S, Keye P, Minguet S, Schadendorf D, Ugurel S, Rafei-Shamsabadi D, Thimme R, Hasselblatt P, Bengsch B, Schell C, Pearce EL, Meiss F, Becher B, Funke-Lorenz C, Placke JM, Apostolova P, Zeiser R. Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity. Cancer Cell 2025; 43:269-291.e19. [PMID: 39933899 DOI: 10.1016/j.ccell.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/30/2024] [Accepted: 01/10/2025] [Indexed: 02/13/2025]
Abstract
Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%-99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%-100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4+IFN-γ+ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.
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Affiliation(s)
- Lukas M Braun
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Sophie Giesler
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roxane Riemer
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nana Talvard-Balland
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sandra Duquesne
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tamina Rückert
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Susanne Unger
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Stefanie Kreutmair
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Melissa Zwick
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Marie Follo
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Alina Hartmann
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Natascha Osswald
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Melchinger
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Stefanie Chapman
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - James A Hutchinson
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Sebastian Haferkamp
- Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
| | - Leopold Torster
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julian Kött
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoffer Gebhardt
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dirk Hellwig
- Department of Nuclear Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Nikolaos Karantzelis
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Till Wallrabenstein
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Theresa Lowinus
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mehtap Yücel
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Niklas Brehm
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Justyna Rawluk
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dietmar Pfeifer
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter Bronsert
- Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Manuel Rogg
- Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sven Mattern
- Institute of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; M3 Research Center, Eberhard Karls University Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Stefano Fusco
- Medizinische Klinik I, Uniklinik Tübingen, Tübingen, Germany
| | - Nisar P Malek
- Medizinische Klinik I, Uniklinik Tübingen, Tübingen, Germany
| | - Stephan Singer
- Institute of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | | | - Fatih Ceteci
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany
| | - Florian R Greten
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Natalie Köhler
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - Justus Duyster
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Gabriele Ihorst
- Clinical Trials Unit, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Silke Lassmann
- Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Philip Keye
- Eye Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Susana Minguet
- Signalling Research Centres BIOSS and CIBSS, Freiburg. Germany. Department of Synthetic Immunology, Faculty of Biology and Centre for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany; National Center for Tumor Diseases (NCT)-West, Campus Essen, & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany
| | - Selma Ugurel
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany
| | - David Rafei-Shamsabadi
- Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter Hasselblatt
- Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bertram Bengsch
- German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - Christoph Schell
- Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Erika L Pearce
- Department of Oncology, The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Frank Meiss
- Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Carolin Funke-Lorenz
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany
| | - Jan-Malte Placke
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany
| | - Petya Apostolova
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Oncology, The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Biomedicine, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Hematology, University Hospital Basel, Basel, Switzerland.
| | - Robert Zeiser
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
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7
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Johnson SD, Pino M, Acharya A, Clain JA, Bose D, Nguyen K, Harper J, Villinger F, Paiardini M, Byrareddy SN. IL-21 and anti-α4β7 dual therapy during ART promotes immunological and microbiome responses in SIV-infected macaques. JCI Insight 2025; 10:e184491. [PMID: 39903521 PMCID: PMC11949015 DOI: 10.1172/jci.insight.184491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 01/28/2025] [Indexed: 02/06/2025] Open
Abstract
Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. Furthermore, ART interruption results in reservoir reactivation and rebound viremia. Both IL-21 and anti-α4β7 improve gut barrier functions, and we hypothesized that combining them would synergize as a dual therapy to improve immunological outcomes in SIV-infected rhesus macaques (RMs). We found no significant differences in CD4+ T cell reservoir size by intact proviral DNA assay. SIV rebounded in both dual-treated and control RMs following analytical therapy interruption (ATI), with time to rebound and initial rebound viremia comparable between groups; however, dual-treated RMs showed slightly better control of viral replication at the latest time points after ATI. Additionally, following ATI, dual-treated RMs showed immunological benefits, including T cell preservation and lower PD-1+ central memory T cell (TCM) frequency. Notably, PD-1+ TCMs were associated with reservoir size, which predicted viral loads (VLs) after ATI. Finally, 16S rRNA-Seq revealed better recovery from dysbiosis in treated animals, and the butyrate-producing Firmicute Roseburia predicted PD-1-expressing TCMs and VLs after ATI. PD-1+ TCMs and gut dysbiosis represent mechanisms of HIV persistence and pathogenesis, respectively. Therefore, combining IL-21 and anti-α4β7 may be an effective therapeutic strategy to improve immunological outcomes for people with HIV.
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Affiliation(s)
- Samuel D. Johnson
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA
| | - Maria Pino
- Division of Microbiology and Immunology, Emory National Primate Research Center (ENPRC), Emory University, Atlanta, Georgia, USA
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA
| | - Julien A. Clain
- Division of Microbiology and Immunology, Emory National Primate Research Center (ENPRC), Emory University, Atlanta, Georgia, USA
| | - Deepanwita Bose
- New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, USA
| | - Kevin Nguyen
- Division of Microbiology and Immunology, Emory National Primate Research Center (ENPRC), Emory University, Atlanta, Georgia, USA
| | - Justin Harper
- Division of Microbiology and Immunology, Emory National Primate Research Center (ENPRC), Emory University, Atlanta, Georgia, USA
| | - Francois Villinger
- New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, USA
| | - Mirko Paiardini
- Division of Microbiology and Immunology, Emory National Primate Research Center (ENPRC), Emory University, Atlanta, Georgia, USA
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Siddappa N. Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA
- Department of Genetics, Cell Biology and Anatomy, and
- Department of Biochemistry and Molecular Biology, UNMC, Omaha, Nebraska, USA
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8
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Reschke R, Sullivan RJ, Lipson EJ, Enk AH, Gajewski TF, Hassel JC. Targeting molecular pathways to control immune checkpoint inhibitor toxicities. Trends Immunol 2025; 46:61-73. [PMID: 39732529 DOI: 10.1016/j.it.2024.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/31/2024] [Accepted: 11/20/2024] [Indexed: 12/30/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are frequently associated with immune-related adverse events (irAEs). This article offers a novel synthesis of findings from both preclinical and clinical studies, focusing on the molecular mechanisms driving irAEs across diverse organ systems. It examines key immune cells, such as T cell subsets and myeloid cells, which are instrumental in irAE pathogenesis, alongside an in-depth analysis of cytokine signaling [interleukin (IL)-6, IL-17, IL-4), interferon γ (IFN-γ), IL-1β, tumor necrosis factor α (TNF-α)], integrin-mediated interactions [integrin subunits αITGA)4 and ITGB7], and microbiome-related factors that contribute to irAE pathology. This exploration of modifiable pathways uncovers new opportunities to mitigate irAEs by using available antibodies (Abs) that target key inflammatory molecules across tumor types, while ideally preserving the antitumor efficacy of ICIs.
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Affiliation(s)
- Robin Reschke
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Core Center Heidelberg, 69120 Heidelberg, Germany.
| | - Ryan J Sullivan
- Mass General Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA
| | - Evan J Lipson
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Alexander H Enk
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas F Gajewski
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60612, USA; Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
| | - Jessica C Hassel
- Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and University Hospital Heidelberg, Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Core Center Heidelberg, 69120 Heidelberg, Germany.
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9
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Gautam M, Jahagirdar V, Mahadevia H, Sanders K, Campbell JP, Sylvestre PB, Chhabra R, Clarkston W, Jonnalagadda SS. Double Whammy: A Case Report of Immune Checkpoint Inhibitor Colitis and Concomitant Cytomegalovirus Colitis in a Patient on Nivolumab. ACG Case Rep J 2025; 12:e01569. [PMID: 39734389 PMCID: PMC11671063 DOI: 10.14309/crj.0000000000001569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 11/07/2024] [Indexed: 12/31/2024] Open
Abstract
Immune checkpoint inhibitors commonly cause gastrointestinal immune-related adverse effects. These patients also carry an increased risk of concomitant infections. This 66-year-old man with immune checkpoint inhibitor colitis was discovered to have concurrent Yersinia and Cytomegalovirus colitis. Such infections may mimic or complicate disease course. Hence, clinicians must monitor patient symptoms, have a low threshold for infectious testing and colonoscopy, and consider treatment strategies to mitigate their risk.
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Affiliation(s)
- Misha Gautam
- Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO
| | - Vinay Jahagirdar
- Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO
| | - Himil Mahadevia
- Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, MO
| | - Kimberly Sanders
- Gastroenterology and Hepatology, University of Missouri-Kansas City School of Medicine, Kansas City, MO
| | - John P. Campbell
- Gastroenterology, Saint Luke's Hospital of Kansas City, Kansas City, MO
| | | | - Rajiv Chhabra
- Gastroenterology and Hepatology, University of Missouri-Kansas City School of Medicine, Kansas City, MO
- Gastroenterology, Saint Luke's Hospital of Kansas City, Kansas City, MO
| | - Wendell Clarkston
- Gastroenterology and Hepatology, University of Missouri-Kansas City School of Medicine, Kansas City, MO
- Gastroenterology, Saint Luke's Hospital of Kansas City, Kansas City, MO
| | - Sreenivasa S. Jonnalagadda
- Gastroenterology and Hepatology, University of Missouri-Kansas City School of Medicine, Kansas City, MO
- Gastroenterology, Saint Luke's Hospital of Kansas City, Kansas City, MO
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10
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Wang S, Wang H. Treatment of immune checkpoint inhibitor-related colitis: a narrative review. Transl Cancer Res 2024; 13:7002-7014. [PMID: 39816545 PMCID: PMC11729759 DOI: 10.21037/tcr-24-2150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 12/17/2024] [Indexed: 01/18/2025]
Abstract
Background and Objective Cancer is one of the most difficult diseases facing modern medicine, and increasing amounts of research and clinical treatments are being applied to the treatment of cancer. Immunotherapy, particularly immune checkpoint inhibitor (ICI) therapy, has revolutionized the treatment and overall survival of patients with several different types of cancer. Approximately one-third of patients treated with ICIs may experience immune-related adverse events (irAEs). Immune checkpoint inhibitor-associated colitis (ICIC) is the most common irAE with an incidence of approximately 8-10%, ICIC usually presents as watery or bloody diarrhea, and if the symptoms are severe, ICI treatment must be interrupted or even terminated. This review summarizes the epidemiology, pathogenesis, clinical characteristics, and therapies of ICIC, focusing on the use of biologics, in order to propose treatment options in different situations to control immune checkpoint inhibitor-related colitis as soon as possible. Methods To find relevant articles for this narrative review paper, a combination of keywords such as immune checkpoint inhibitor-related colitis, corticosteroids, biologics were searched for in PubMed databases. Key Content and Findings The pathogenesis of ICIC is complex and primarily involves antitumor effects and indirect damage to colonic tissues, as well as the activation of specific proinflammatory pathways. Corticosteroids (CSs) are the first line of treatment for ICIC, but steroid-refractory or steroid-resistant cases often occur. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Conclusions Biologics are currently recommended for the treatment of ICIC but are usually used as a supplement after the failure of first-line CS therapy. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Biologics (alone or in combination with CS) should be considered as an early therapy option for high-risk patients rather than just an escalation after a failure to respond to CS.
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Affiliation(s)
- Shiyang Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hanping Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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11
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Shatila M, Zhang HC, Shirwaikar Thomas A, Machado AP, Naz S, Mittal N, Catinis C, Varatharajalu K, Colli Cruz C, Lu E, Wu D, Brahmer JR, Carbonnel F, Hanauer SB, Lashner B, Schneider B, Thompson JA, Obeid M, Farris DP, Wang Y. Systematic review of immune checkpoint inhibitor-related gastrointestinal, hepatobiliary, and pancreatic adverse events. J Immunother Cancer 2024; 12:e009742. [PMID: 39542654 PMCID: PMC11575294 DOI: 10.1136/jitc-2024-009742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2024] [Indexed: 11/17/2024] Open
Abstract
Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.
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Affiliation(s)
- Malek Shatila
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Anusha Shirwaikar Thomas
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Sidra Naz
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Nitish Mittal
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Christine Catinis
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Krishnavathana Varatharajalu
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Carolina Colli Cruz
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Eric Lu
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Deanna Wu
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Julie R Brahmer
- Department of Thoracic Medical Oncology, Johns Hopkins University, Baltimore, Maryland, USA
| | - Franck Carbonnel
- Department of Gastroenterology, Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Stephen B Hanauer
- Department of Gastroenterology, Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA
| | - Bret Lashner
- Center for Inflammatory Bowel Disease, Cleveland Clinic, Cleveland, Ohio, USA
| | - Bryan Schneider
- Department of Thoracic Medical Oncology, University of Michigan, Ann Arbor, Michigan, UK
| | - John A Thompson
- Department of Medicine, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA
| | - Michel Obeid
- Department of Medicine, Service of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - David P Farris
- Research Medical Library, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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12
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Kim MK, Hwang SW. Endoscopic findings of immune checkpoint inhibitor-related gastrointestinal adverse events. Clin Endosc 2024; 57:725-734. [PMID: 39206499 PMCID: PMC11637655 DOI: 10.5946/ce.2024.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 03/08/2024] [Accepted: 03/11/2024] [Indexed: 09/04/2024] Open
Abstract
The use of immune checkpoint inhibitors (ICIs) for the treatment of various malignancies is increasing. Immune-related adverse events can occur after ICI administration, with gastrointestinal adverse events constituting a significant proportion of these events. When ICI-related diarrhea/colitis is suspected, endoscopic evaluation is recommended to differentiate it from other etiologies and assess the severity of colitis. The distribution of intestinal inflammation in ICI-related colitis demonstrates a high frequency of extensive colitis (23-86%). However, isolated right-sided colitis (3-8%) and ileitis (2-16%) are less prevalent. Endoscopic findings vary and predominantly encompass features indicative of inflammatory bowel disease, including aphthae, ulcers, diffuse or patchy erythema, mucosal edema, loss of vascular pattern, and friability. The presence of ulcers and extensive intestinal inflammation are associated with a reduced response to treatment. Microscopic inflammation can be observed even in endoscopically normal mucosa, underscoring the need for biopsies of seemingly normal mucosa. Histological findings present with acute/chronic inflammation and occasionally exhibit characteristics observed in inflammatory bowel disease, microscopic colitis, or ischemic colitis. The first-line therapeutic choice for ICI-related diarrhea/colitis with a common terminology criteria for adverse events grade of 2 or above is corticosteroids, whereas infliximab and vedolizumab are recommended for refractory cases.
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Affiliation(s)
- Min Kyu Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung Wook Hwang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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13
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Ortiz V, Loeuillard E. Rethinking Immune Check Point Inhibitors Use in Liver Transplantation: Implications and Resistance. Cell Mol Gastroenterol Hepatol 2024; 19:101407. [PMID: 39326581 PMCID: PMC11609388 DOI: 10.1016/j.jcmgh.2024.101407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 09/18/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, including the two most common liver tumors, hepatocellular carcinoma and cholangiocarcinoma, but their use in the peri-transplantation period is controversial. ICI therapy aims to heighten cytotoxic T lymphocytes response against tumors. However, tumor recurrence is common owing to tumor immune response escape involving ablation of CTL response by interfering with antigen presentation, triggering CLT apoptosis and inducing epigenetic changes that promote ICI therapy resistance. ICI can also affect tissue resident memory T cell population, impact tolerance in the post-transplant period, and induce acute inflammation risking graft survival post-transplant. Their interaction with immunosuppression may be key in reducing tumor burden and may thus, require multimodal therapy to treat these tumors. This review summarizes ICI use in the liver transplantation period, their impact on tolerance and resistance, and new potential therapies for combination or sequential treatments for liver tumors.
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Affiliation(s)
- Vivian Ortiz
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri.
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14
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Zoghbi M, Burk KJ, Haroun E, Saade M, Carreras MTC. Immune checkpoint inhibitor-induced diarrhea and colitis: an overview. Support Care Cancer 2024; 32:680. [PMID: 39311981 PMCID: PMC11420271 DOI: 10.1007/s00520-024-08889-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as an integral component of the management of various cancers and have contributed to significant improvements in overall survival. Most available ICIs target anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), and anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD1/PDL1). Gastrointestinal immune-related adverse events remain a common complication of ICIs. The predominant manifestations include diarrhea and colitis, which often manifest concurrently as immune-mediated diarrhea and colitis (IMDC). Risk factors for developing these side effects include baseline gut microbiota, preexisting autoimmune disorders, such as inflammatory bowel disease, and type of neoplasm. The hallmark symptom of colitis is diarrhea which may be accompanied by mucus or blood in stools. Patients may also experience abdominal pain, fever, vomiting, and nausea. If not treated rapidly, ICI-induced colitis can lead to serious life-threatening complications. Current management is based on corticosteroids as first-line, and immunosuppressants like infliximab or vedolizumab for refractory cases. Microbiota transplantation and specific cytokines and lymphocyte replication inhibitors are being investigated. Optimal patient care requires maintaining a balance between treatment toxicity and efficacy, hence the aim of this review is to enhance readers' comprehension of the gastrointestinal adverse events associated with ICIs, particularly IMDC. In addition to identifying the risk factors, we discuss the incidence, clinical presentation, workup, and management options of IMDC.
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Affiliation(s)
- Marianne Zoghbi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Kathryn J Burk
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elio Haroun
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1100, Lebanon
| | - Maria Saade
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1100, Lebanon
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15
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Kim H, Shin YE, Yoo HJ, Kim JY, Yoo JJ, Kim SG, Kim YS. Atezolizumab-Induced Ulcerative Colitis in Patient with Hepatocellular Carcinoma: Case Report and Literature Review. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1422. [PMID: 39336463 PMCID: PMC11433725 DOI: 10.3390/medicina60091422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/30/2024]
Abstract
Background and Objectives: Immune check inhibitor (ICI) colitis is one of most common and adverse side effects of ICI. However, there was no case report of ulcerative colitis (UC)-mimicking colitis after atezolizumab use in hepatocellular carcinoma (HCC) to our knowledge. Materials and Methods: We would like to introduce the case of a patient with Stage IV HCC who complained of abdominal pain, diarrhea and rectal bleeding after two cycles of atezolizumab/bevacizumab chemotherapy and was then diagnosed with UC-mimicking colitis. Results: Endoscopy revealed typical findings of UC, suggesting diagnosis of UC-mimicking colitis. The patient was treated with systemic steroids and oral mesalamine, which significantly improved his symptoms, which were also supported by endoscopic findings. The patient resumed chemotherapy with atezolizumab and bevacizumab without any interruption to the chemotherapy schedule. Conclusions: Early endoscopic evaluation is pivotal to diagnosing UC-mimicking colitis. If diagnosed, UC-based treatments such as steroids and mesalamine should be strongly considered. Given previous reports of inflammatory bowel disease (IBD) flare-ups after immunotherapy, routine lower endoscopy, performed together with upper endoscopy before atezolizumab/bevacizumab therapy, is promising to patients.
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Affiliation(s)
- Hyuk Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, Republic of Korea; (H.K.); (Y.E.S.)
| | - Yoon E Shin
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, Republic of Korea; (H.K.); (Y.E.S.)
| | - Hye-Jin Yoo
- Department of Internal Medicine, Soonchunhyang University School of Medicine, Cheonan 31151, Republic of Korea; (H.-J.Y.); (J.-Y.K.)
| | - Jae-Young Kim
- Department of Internal Medicine, Soonchunhyang University School of Medicine, Cheonan 31151, Republic of Korea; (H.-J.Y.); (J.-Y.K.)
| | - Jeong-Ju Yoo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, Republic of Korea; (S.G.K.); (Y.S.K.)
| | - Sang Gyune Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, Republic of Korea; (S.G.K.); (Y.S.K.)
| | - Young Seok Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon 14584, Republic of Korea; (S.G.K.); (Y.S.K.)
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16
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Grice S, Olsson-Brown A, Naisbitt DJ, Hammond S. Immunological Drug-Drug Interactions Affect the Efficacy and Safety of Immune Checkpoint Inhibitor Therapies. Chem Res Toxicol 2024; 37:1086-1103. [PMID: 38912648 PMCID: PMC11256900 DOI: 10.1021/acs.chemrestox.4c00067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 06/02/2024] [Accepted: 06/07/2024] [Indexed: 06/25/2024]
Abstract
With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug-drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.
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Affiliation(s)
- Sophie Grice
- Department
of Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
| | - Anna Olsson-Brown
- Department
of Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
- Sussex
Cancer Centre, University Hospitals Sussex, Brighton BN2 5BD, U.K.
| | - Dean J. Naisbitt
- Department
of Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
| | - Sean Hammond
- Department
of Molecular and Clinical Pharmacology, Institute of Translational
Medicine, University of Liverpool, Liverpool L69 3GE, U.K.
- ApconiX, Alderley Edge SK10 4TG, U.K.
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17
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Park M, Kim JW. Updates on the mechanisms of toxicities associated with monoclonal antibodies targeting growth factor signaling and immune cells in cancer. Toxicol Res 2024; 40:335-348. [PMID: 38911540 PMCID: PMC11187026 DOI: 10.1007/s43188-024-00233-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/12/2024] [Accepted: 03/15/2024] [Indexed: 06/25/2024] Open
Abstract
Monoclonal antibody (mAb)-based immunotherapy currently is considered to be an optimal therapeutic approach to cancer treatment, either in combination with surgery, radiation, and/or chemotherapy or alone. Various solid tumors and hematological malignancies have been characterized by distinct molecular targets, which could be utilized as innovative anticancer agents. Notably, receptor tyrosine kinases, including HER2, EGFR, VEGFR, and PDGFR, which act as receptors for growth factors, serve as crucial target proteins, expanding their role in the cancer therapeutic market. In contrast to conventional anticancer agents that directly target cancer cells, the advent of immunotherapy introduces novel approaches, such as immune checkpoint blockers (ICBs) and mAbs targeting surface antigens on immune cells in hematological malignancies and lymphomas. While these immunotherapies have mitigated the acquired resistance observed in traditional targeted therapies, they also exhibit diverse toxicities. Herein, this review focuses on describing the well-established toxicities and newly proposed mechanisms of monoclonal antibody toxicity in recent studies. Understanding these molecular mechanisms is indispensable to overcoming the limitations of mAbs-based therapies, facilitating the development of innovative anticancer agents, and uncovering novel indications for cancer treatment in the future.
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Affiliation(s)
- Miso Park
- College of Pharmacy, Kangwon National University, Chuncheon, Gangwon-do Republic of Korea
| | - Ji Won Kim
- Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, Jeju-do, Republic of Korea
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18
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Tauseef A, Zafar M, Siddiqui SAH, Dufani J, DeVrieze B, Mirza M, Thirumalareddy J, Sood A, Mirza M. Management of immune check-point inhibitor-associated colitis in patients with advanced metastatic cancers: A review article. J Family Med Prim Care 2024; 13:2562-2567. [PMID: 39070997 PMCID: PMC11272031 DOI: 10.4103/jfmpc.jfmpc_1438_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/28/2023] [Accepted: 01/12/2024] [Indexed: 07/30/2024] Open
Abstract
Immune check-point inhibitors (ICPi) are immunomodulating agents, which have revolutionized the management of advanced metastatic cancers. Being immunomodulating agents, they are predisposed to causing colitis. This descriptive review article emphasized on the management of ICPi-associated colitis in advanced metastatic cancers. We used PubMed, Google Scholar, Scopus, and Embase databases for literature review, and terminologies commonly searched were "management," "immune check-point inhibitors," "colitis," "metastatic," "cancers," "literature," and "review." We reviewed a total of 11 articles done in the last 15 years relevant to ICPi colitis and its management; all the articles showed that diarrhea and colitis are the most common adverse effects observed in patients on ICPi, but prior to establishing the diagnosis of ICPi-causing colitis, possibility of Clostridium difficle or cytomegalovirus infections should be ruled out. Once the diagnosis of ICPi colitis is established, treatment should be started depending upon the severity of colitis. In mild severity, discontinuation of ICPi can resolve the symptoms but, in most of the patients with moderate to high severity of colitis, corticosteroids are considered a cornerstone treatment. Patients unresponsive to steroid treatment should be re-evaluated for infections after which anti-TNF therapy-infliximab or vedolizumab, cyclosporine, mycophenolate mofetil-can be considered.
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Affiliation(s)
- Abubakar Tauseef
- Department of Internal Medicine, Creighton University School of Medicine, United States
| | - Maryam Zafar
- Graduate of Dow University of Health Sciences, Pakistan
| | | | - Jalal Dufani
- Hospitalist at Bergan Mercy Medical Center, United States
| | - Bradley DeVrieze
- Department of Internal Medicine, Creighton University School of Medicine, United States
| | - Muazzam Mirza
- Hospitalist at Bergan Mercy Medical Center, United States
| | | | - Akshat Sood
- Hospitalist at Bergan Mercy Medical Center, United States
| | - Mohsin Mirza
- Department of Internal Medicine, Creighton University School of Medicine, United States
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19
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Del Gaudio A, Di Vincenzo F, Petito V, Giustiniani MC, Gasbarrini A, Scaldaferri F, Lopetuso LR. Focus on Immune Checkpoint Inhibitors-related Intestinal Inflammation: From Pathogenesis to Therapeutical Approach. Inflamm Bowel Dis 2024; 30:1018-1031. [PMID: 37801695 PMCID: PMC11144981 DOI: 10.1093/ibd/izad229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Indexed: 10/08/2023]
Abstract
Recently, antitumor immunotherapies have witnessed a breakthrough with the emergence of immune checkpoint inhibitors (ICIs) including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. Unfortunately, the use of ICIs has also led to the advent of a novel class of adverse events that differ from those of classic chemotherapeutics and are more reminiscent of autoimmune diseases, the immune-related adverse events (IRAEs). Herein, we performed an insight of the main IRAEs associated with ICIs, focusing on gastroenterological IRAEs and specifically on checkpoint inhibitor colitis, which represents the most widely reported IRAE to date. We comprehensively dissected the current evidence regarding pathogenesis, diagnosis, and management of ICIs-induced colitis, touching upon also on innovative therapies.
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Affiliation(s)
- Angelo Del Gaudio
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Federica Di Vincenzo
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Valentina Petito
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | | | - Antonio Gasbarrini
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Franco Scaldaferri
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Loris Riccardo Lopetuso
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, Chieti, 66100, Italy
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, 66100, Italy
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20
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Thomas MF, Slowikowski K, Manakongtreecheep K, Sen P, Samanta N, Tantivit J, Nasrallah M, Zubiri L, Smith NP, Tirard A, Ramesh S, Arnold BY, Nieman LT, Chen JH, Eisenhaure T, Pelka K, Song Y, Xu KH, Jorgji V, Pinto CJ, Sharova T, Glasser R, Chan P, Sullivan RJ, Khalili H, Juric D, Boland GM, Dougan M, Hacohen N, Li B, Reynolds KL, Villani AC. Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis. Nat Med 2024; 30:1349-1362. [PMID: 38724705 PMCID: PMC11673812 DOI: 10.1038/s41591-024-02895-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 03/01/2024] [Indexed: 05/23/2024]
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2Hi CD8 T cells. Cytotoxic GNLYHi CD4 T cells, recirculating ITGB2Hi CD8 T cells and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 therapy compared to anti-PD-1 therapy. Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis.
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Affiliation(s)
- Molly Fisher Thomas
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
- Harvard Medical School, Boston, MA, USA.
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- Division of Gastroenterology, Department of Medicine, Oregon Health and Sciences University, Portland, OR, USA.
- Department of Cell, Developmental, and Cancer Biology, Oregon Health and Sciences University, Portland, OR, USA.
| | - Kamil Slowikowski
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
- Harvard Medical School, Boston, MA, USA.
| | - Kasidet Manakongtreecheep
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Pritha Sen
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Transplant, Oncology, and Immunocompromised Host Group, Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nandini Samanta
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Jessica Tantivit
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Mazen Nasrallah
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of Rheumatology, Department of Medicine, North Shore Physicians Group, Mass General Brigham Healthcare Center, Lynn, MA, USA
| | - Leyre Zubiri
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Neal P Smith
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Alice Tirard
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Swetha Ramesh
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Benjamin Y Arnold
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Linda T Nieman
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jonathan H Chen
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Thomas Eisenhaure
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Karin Pelka
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA
| | - Yuhui Song
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
| | - Katherine H Xu
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
| | - Vjola Jorgji
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | | | - Tatyana Sharova
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Rachel Glasser
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - PuiYee Chan
- Harvard Medical School, Boston, MA, USA
- Clinical Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Ryan J Sullivan
- Harvard Medical School, Boston, MA, USA
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Hamed Khalili
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Dejan Juric
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Genevieve M Boland
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Michael Dougan
- Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Nir Hacohen
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Bo Li
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Genentech, South San Francisco, CA, USA
| | - Kerry L Reynolds
- Harvard Medical School, Boston, MA, USA
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Alexandra-Chloé Villani
- Department of Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
- Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
- Harvard Medical School, Boston, MA, USA.
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21
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Lin J, Lin ZQ, Zheng SC, Chen Y. Immune checkpoint inhibitor-associated gastritis: Patterns and management. World J Gastroenterol 2024; 30:1941-1948. [PMID: 38681126 PMCID: PMC11045486 DOI: 10.3748/wjg.v30.i14.1941] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/23/2024] [Accepted: 03/28/2024] [Indexed: 04/12/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) are widely used due to their effectiveness in treating various tumors. Immune-related adverse events (irAEs) are defined as adverse effects resulting from ICI treatment. Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects, such as diarrhea and colitis, which may lead to the cessation of ICIs. Although irAE gastritis is rarely reported, it may lead to serious complications such as gastrorrhagia. Furthermore, irAE gastritis is often difficult to identify early due to its diverse symptoms. Although steroid hormones and immunosuppressants are commonly used to reverse irAEs, the best regimen and dosage for irAE gastritis remains uncertain. In addition, the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered. In this editorial, strategies such as early identification, pathological diagnosis, management interventions, and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.
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Affiliation(s)
- Jing Lin
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350000, Fujian Province, China
| | - Zhong-Qiao Lin
- Phase I Clinical Trial Ward, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350000, Fujian Province, China
| | - Shi-Cheng Zheng
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350000, Fujian Province, China
| | - Yu Chen
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou 350000, Fujian Province, China
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22
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallego-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:401-432. [PMID: 38228461 DOI: 10.1016/j.gastrohep.2023.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/28/2023] [Accepted: 10/19/2023] [Indexed: 01/18/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
- Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona (UAB), Department of Medicine, Spain.
| | - Sabela Carballal
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Universitat de Barcelona, Spain
| | - Álvaro Díaz-González
- Gastroenterology Department, Grupo de Investigación Clínica y Traslacional en Enfermedades Digestivas, Instituto de Investigación Valdecilla (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Míriam Mañosa
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | | | - Joaquín Cubiella
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitario de Ourense, Grupo de Investigación en Oncología Digestiva-Ourense, Spain
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - María Varela
- Gastroenterology Department, Hospital Universitario Central de Asturias, IUOPA, ISPA, FINBA, University of Oviedo, Oviedo, Spain
| | - Luis Menchén
- Servicio de Aparato Digestivo - CEIMI, Instituto de Investigación Sanitaria Gregorio, Marañón, Spain; Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Cancer Center Clinica Universidad de Navarra, Pamplona-Madrid, Spain
| | - Ana Fernández-Montes
- Medical Oncology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Francisco Mesonero
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Universidad de Alcalá de Henares, Spain
| | - Miguel Ángel Rodríguez-Gandía
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS), Madrid, Spain
| | - Fernando Rivera
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - María-Carlota Londoño
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat de Barcelona, Spain; Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Spain
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23
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Park JS, Cresci GAM. Dysfunctional intestinal microvascular endothelial cells: Insights and therapeutic implications in gastrointestinal inflammation. IMMUNOMETABOLISM (COBHAM, SURREY) 2024; 6:e00043. [PMID: 38818514 PMCID: PMC11136270 DOI: 10.1097/in9.0000000000000043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/01/2024] [Indexed: 06/01/2024]
Abstract
The intestinal microvascular endothelium plays a crucial role in orchestrating host responses to inflammation within the gastrointestinal tract. This review delves into the unique aspects of intestinal microvascular endothelial cells, distinct from those of larger vessels, in mediating leukocyte recruitment, maintaining barrier integrity, and regulating angiogenesis during inflammation. Specifically, their role in the pathogenesis of inflammatory bowel diseases, where dysregulated endothelial functions contribute to the disease progression, is reviewed. Furthermore, this review discusses the isolation technique for these cells and commonly used adhesion molecules for in vitro and in vivo experiments. In addition, we reviewed the development and therapeutic implications of a biologic agent targeting the interaction between α4β7 integrin on T lymphocytes and mucosal addressin cellular adhesion molecule-1 on gut endothelium. Notably, vedolizumab, a humanized monoclonal antibody against α4β7 integrin, has shown promising outcomes in inflammatory bowel diseases and other gastrointestinal inflammatory conditions, including chronic pouchitis, immune checkpoint inhibitor-induced colitis, and acute cellular rejection post-intestinal transplantation.
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Affiliation(s)
- Ji Seok Park
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gail A. M. Cresci
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children’s Hospital, Cleveland, OH, USA
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24
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Middha P, Thummalapalli R, Betti MJ, Yao L, Quandt Z, Balaratnam K, Bejan CA, Cardenas E, Falcon CJ, Faleck DM, Gubens MA, Huntsman S, Johnson DB, Kachuri L, Khan K, Li M, Lovly CM, Murray MH, Patel D, Werking K, Xu Y, Zhan LJ, Balko JM, Liu G, Aldrich MC, Schoenfeld AJ, Ziv E. Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis. Nat Commun 2024; 15:2568. [PMID: 38531883 PMCID: PMC10966072 DOI: 10.1038/s41467-023-44512-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 12/15/2023] [Indexed: 03/28/2024] Open
Abstract
Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10-03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10-04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.
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Affiliation(s)
- Pooja Middha
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Rohit Thummalapalli
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael J Betti
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lydia Yao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Zoe Quandt
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
| | | | - Cosmin A Bejan
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eduardo Cardenas
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Christina J Falcon
- Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David M Faleck
- Gastroenterology, Hepatology & Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Matthew A Gubens
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Scott Huntsman
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Linda Kachuri
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University of Medicine, Stanford, CA, USA
| | - Khaleeq Khan
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Min Li
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Christine M Lovly
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA
| | - Megan H Murray
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Kristin Werking
- Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yaomin Xu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Luna Jia Zhan
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Justin M Balko
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Geoffrey Liu
- Princess Margaret Cancer Centre, Toronto, ON, Canada
- Temerty School of Medicine, Toronto, ON, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Melinda C Aldrich
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Adam J Schoenfeld
- Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Elad Ziv
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
- Center for Genes, Environment and Health, University of California San Francisco, San Francisco, CA, USA.
- Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
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25
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Martinez Perez P, Hanna L, Jaynes E, Gwiggner M. Infliximab rescue therapy in a case of severe granulomatous colitis associated with rituximab use. BMJ Case Rep 2024; 17:e257729. [PMID: 38423571 PMCID: PMC10910684 DOI: 10.1136/bcr-2023-257729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2024] Open
Abstract
Colitis occurs in about 4% of individuals treated with rituximab. Optimal management of rituximab-induced colitis, which does not improve with cessation of the drug and supportive care alone, is poorly defined due to limited evidence. Severe refractory disease can lead to colectomy. We present a case of suspected rituximab-induced colitis occurring in a woman in her 70s suffering from rheumatoid arthritis. The patient achieved full clinical, endoscopic and histological remission of colitis with infliximab therapy. The use of biological therapy to treat rituximab-induced colitis can be a potentially organ-saving rescue therapy; however, it must be balanced against the increased risks of immunosuppression in patients already exposed to rituximab. While more evidence is required to fully understand the efficacy and risks of antitumour necrosis factor therapy in this scenario, our case provides an example of the successful use of infliximab for rituximab-induced colitis, which likely helped the patient avoid a colectomy.
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Affiliation(s)
| | - Luke Hanna
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Eleanor Jaynes
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Markus Gwiggner
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
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26
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Velikova T, Krastev B, Gulinac M, Zashev M, Graklanov V, Peruhova M. New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis. World J Clin Cases 2024; 12:1050-1062. [PMID: 38464930 PMCID: PMC10921308 DOI: 10.12998/wjcc.v12.i6.1050] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/20/2023] [Accepted: 01/19/2024] [Indexed: 02/20/2024] Open
Abstract
Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.
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Affiliation(s)
- Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Boris Krastev
- Medical Center Nadezhda, Medical Center Nadezhda, Sofia 1407, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- General and Clinical Pathology, Medical University of Plovdiv, Plovdiv 4002, Bulgaria
| | - Miroslav Zashev
- Department of General Surgery, University Hospital “Heart and Brain”, Burgas 8000, Bulgaria
| | - Vasko Graklanov
- First Department of Internal Diseases, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
- Department of Hematology, University Hospital “St. George”, Plovdiv 4000, Bulgaria
| | - Milena Peruhova
- Division of Gastroenterology, University Hospital “Heart and Brain”, Burgas 1000, Bulgaria
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallgo-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:83-113. [PMID: 38226597 DOI: 10.17235/reed.2024.10250/2024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
| | | | | | - Miriam Mañosa
- Gastroenterology, Hospital Universitari Germans Trias i Pujol
| | | | | | | | - María Varela
- Gastroenterology, Hospital Universitario Central de Asturias
| | - Luis Menchén
- Digestive Diseases, Instituto de Investigación Sanitaria Gregorio Marañón
| | | | | | | | | | - Fernando Rivera
- Hospital Universitario Marqués de Valdecilla, Medical Oncology
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Ishihara H, Watanabe T, Kumei S, Kume K, Yoshikawa I, Harada M. A case of refractory immune checkpoint inhibitor-induced colitis improved by the treatment with vedolizumab and granulocyte-monocyte apheresis combination therapy. Clin J Gastroenterol 2024; 17:46-51. [PMID: 38041760 DOI: 10.1007/s12328-023-01887-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/23/2023] [Indexed: 12/03/2023]
Abstract
A 68-year-old man developed immune-related adverse event (irAE) colitis after the initiation of nivolumab and ipilimumab combination therapy for malignant melanoma. We diagnosed the patient with grade 3 irAE colitis and started prednisolone (1 mg/kg/day). Although the symptom improved once, it worsened along with the tapering of prednisolone. Therefore, we started infliximab (IFX). However, symptoms did not improve after two doses of IFX. We discontinued IFX and initiated vedolizumab (VED). Because VED alone did not improve the symptom, we started granulocyte-monocyte apheresis (GMA). Twelve weeks after the onset, the colitis was in remission. Therefore, in addition to vedolizumab, GMA may be considered in cases refractory to treatment.
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Affiliation(s)
- Hikaru Ishihara
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Tatsuyuki Watanabe
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Shinsuke Kumei
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Keiichiro Kume
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Ichiro Yoshikawa
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Masaru Harada
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
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29
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Gravina AG, Pellegrino R, Esposito A, Cipullo M, Romeo M, Palladino G, Iodice P, Federico A, Troiani T. The JAK-STAT Pathway as a Therapeutic Strategy in Cancer Patients with Immune Checkpoint Inhibitor-Induced Colitis: A Narrative Review. Cancers (Basel) 2024; 16:611. [PMID: 38339367 PMCID: PMC10854551 DOI: 10.3390/cancers16030611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/28/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Immunotherapy has emerged as a pivotal component in the treatment of various malignancies, encompassing lung, skin, gastrointestinal, and head and neck cancers. The foundation of this therapeutic approach lies in immune checkpoint inhibitors (ICI). While ICIs have demonstrated remarkable efficacy in impeding the neoplastic progression of these tumours, their use may give rise to substantial toxicity, notably in the gastrointestinal domain, where ICI colitis constitutes a significant aspect. The optimal positioning of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway inhibitors in the therapeutic management of ICI colitis remains unclear. Numerous reports have highlighted notable improvements in ICI colitis through the application of pan-JAK-STAT inhibitors, with tofacitinib, in particular, reporting evident clinical remission of colitis. The precise mechanism by which JAK-STAT inhibitors may impact the pathogenetic process of ICI colitis remains inadequately understood. However, there is speculation regarding their potential role in modulating memory resident CD8+ T lymphocytes. The elucidation of this mechanism requires further extensive and robust evidence, and ongoing JAK-STAT-based trials are anticipated to contribute valuable insights.
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Affiliation(s)
- Antonietta Gerarda Gravina
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. de Crecchio, 80138 Naples, Italy
| | - Raffaele Pellegrino
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. de Crecchio, 80138 Naples, Italy
| | - Alfonso Esposito
- Oncology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. de Crecchio, 80138 Naples, Italy
| | - Marina Cipullo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. de Crecchio, 80138 Naples, Italy
| | - Mario Romeo
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. de Crecchio, 80138 Naples, Italy
| | - Giovanna Palladino
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. de Crecchio, 80138 Naples, Italy
| | - Patrizia Iodice
- Oncology Division, AORN Ospedali Dei Colli, Monaldi Hospital, Via L. Bianchi, 80131 Naples, Italy
| | - Alessandro Federico
- Hepatogastroenterology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. de Crecchio, 80138 Naples, Italy
| | - Teresa Troiani
- Oncology Division, Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. de Crecchio, 80138 Naples, Italy
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Dougan M, Nguyen LH, Buchbinder EI, Lazarus HM. Sargramostim for Prophylactic Management of Gastrointestinal Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy for Cancer. Cancers (Basel) 2024; 16:501. [PMID: 38339253 PMCID: PMC10854719 DOI: 10.3390/cancers16030501] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/22/2024] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.
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Affiliation(s)
- Michael Dougan
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (M.D.); (E.I.B.)
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;
| | - Long H. Nguyen
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Elizabeth I. Buchbinder
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; (M.D.); (E.I.B.)
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Hillard M. Lazarus
- Department of Medicine, Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH 44106, USA
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Daetwyler E, Wallrabenstein T, König D, Cappelli LC, Naidoo J, Zippelius A, Läubli H. Corticosteroid-resistant immune-related adverse events: a systematic review. J Immunother Cancer 2024; 12:e007409. [PMID: 38233099 PMCID: PMC10806650 DOI: 10.1136/jitc-2023-007409] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2023] [Indexed: 01/19/2024] Open
Abstract
Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.
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Affiliation(s)
- Eveline Daetwyler
- Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
| | - Till Wallrabenstein
- Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
- Division of Hematology and Medical Oncology, University Medical Center Freiburg, Freiburg, Germany
| | - David König
- Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
| | - Laura C Cappelli
- Divison of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Alfred Zippelius
- Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Heinz Läubli
- Division of Medical Oncology, University Hospital Basel, Basel, Switzerland
- Department of Biomedicine, University of Basel, Basel, Switzerland
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32
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Gómez Escudero O. Enterocolitis and other immunotherapy and targeted therapy-related gastrointestinal manifestations: A review for gastroenterologist. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2024; 89:89-105. [PMID: 38485558 DOI: 10.1016/j.rgmxen.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 11/08/2023] [Indexed: 04/20/2024]
Abstract
New oncologic treatments, particularly immunotherapy (IT), have revolutionized the treatment of advanced-stage malignant tumors. Immune checkpoint inhibitors are the main form of IT and act by increasing T cell activity and the organism's immune response against neoplastic cells. Targeted therapy is another form of IT that acts by inhibiting oncogenes or inflammation signaling and tumor angiogenesis pathways. However, these mechanisms of tumor destruction can interfere with the host's immune self-tolerance or with the mechanisms of epithelial tissue repair and predispose to immune system-mediated adverse events that can affect multiple organs, including the digestive tract. The gastrointestinal manifestations of damage caused by IT can range from low-grade mucositis to ulceration, and in some cases, necrosis and perforation. Any part of the gastrointestinal tract can be affected, but there is greater involvement of the small bowel and colon, with a pattern similar to that seen in inflammatory bowel disease. The most common clinical manifestation is chronic diarrhea. The differential diagnosis includes enteropathogenic infections, especially those caused by opportunistic microorganisms; adverse drug reactions; and other inflammatory and malabsorption disorders. Treatment is guided by damage severity. Mild cases can be treated with antidiarrheals and rehydration in the outpatient setting; moderate cases with hospitalization, systemic steroids, and temporary suspension of IT; and severe cases with immunosuppressants or biologic agents and definitive suspension of IT.
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Affiliation(s)
- O Gómez Escudero
- Clínica de Gastroenterología, Endoscopia Digestiva y Motilidad Gastrointestinal «Endoneurogastro», Hospital Ángeles, Puebla, Mexico.
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Gómez-Escudero O. Enterocolitis y otras manifestaciones de toxicidad gastrointestinal asociada a inmunoterapia y terapia blanco: una revisión para el gastroenterólogo. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2024; 89:89-105. [DOI: 10.1016/j.rgmx.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ding M, Zhang X, Wang J, Gao F, Zheng X, Yuan J, Qi X. Treatment and outcomes of immune checkpoint inhibitors-associated colitis/diarrhea: A systematic review and meta-analysis. Dig Liver Dis 2023; 55:1621-1631. [PMID: 36894390 DOI: 10.1016/j.dld.2023.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have improved the outcomes of cancer patients. However, ICIs often lead to colitis/diarrhea. This study aimed to assess the treatment of ICIs-associated colitis/diarrhea and outcomes. METHODS PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies which investigated the treatment and outcomes of colitis/diarrhea developing in patients who received ICIs. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea as well as the pooled rates of response to treatment, mortality, and ICIs permanent discontinuation and restarts in patients with ICIs-associated colitis/diarrhea were estimated using a random-effects model. RESULTS Among the 11,492 papers initially identified, 27 studies were included. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea were 17%, 3%, 17%, 13%, and 15%, respectively. The pooled rates of overall response, response to corticosteroid therapy, and response to biological agents were 88%, 50%, and 96%, respectively. The pooled short-term mortality in patients with ICIs-associated colitis/diarrhea was 2%. The pooled incidences of ICIs permanent discontinuation and restarts were 43% and 33%, respectively. CONCLUSION ICIs-associated colitis/diarrhea is common, but rarely lethal. Half of them are responsive to corticosteroid therapy. There is a fairly high rate of response to biological agents in steroid-refractory colitis/diarrhea patients.
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Affiliation(s)
- Min Ding
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China
| | - Xianxian Zhang
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Jing Wang
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Gastroenterology, The 960th Hospital of the PLA, Jinan, China
| | - Fangbo Gao
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaojie Zheng
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China
| | - Jinqiu Yuan
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xingshun Qi
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
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35
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Lo JW, Cozzetto D, Alexander JL, Danckert NP, Madgwick M, Knox N, Sieh JYX, Olbei M, Liu Z, Ibraheim H, Blanco JM, Kudo H, Seoane RC, Possamai LA, Goldin R, Marchesi J, Korcsmaros T, Lord GM, Powell N. Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis. Nat Commun 2023; 14:6719. [PMID: 37872166 PMCID: PMC10593820 DOI: 10.1038/s41467-023-41798-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 09/18/2023] [Indexed: 10/25/2023] Open
Abstract
Immune checkpoint inhibitors (CPIs) are a relatively newly licenced cancer treatment, which make a once previously untreatable disease now amenable to a potential cure. Combination regimens of anti-CTLA4 and anti-PD-1 show enhanced efficacy but are prone to off-target immune-mediated tissue injury, particularly at the barrier surfaces. To probe the impact of immune checkpoints on intestinal homoeostasis, mice are challenged with anti-CTLA4 and anti-PD-1 immunotherapy and manipulation of the intestinal microbiota. The immune profile of the colon of these mice with CPI-colitis is analysed using bulk RNA sequencing, single-cell RNA sequencing and flow cytometry. CPI-colitis in mice is dependent on the composition of the intestinal microbiota and by the induction of lymphocytes expressing interferon-γ (IFNγ), cytotoxicity molecules and other pro-inflammatory cytokines/chemokines. This pre-clinical model of CPI-colitis could be attenuated following blockade of the IL23/IFNγ axis. Therapeutic targeting of IFNγ-producing lymphocytes or regulatory networks, may hold the key to reversing CPI-colitis.
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Affiliation(s)
- Jonathan W Lo
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Domenico Cozzetto
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - James L Alexander
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Nathan P Danckert
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Matthew Madgwick
- Organisms and Ecosystems, Earlham Institute, NR4 7UZ, Norwich, UK
- Gut Microbes and Health Programme, Quadram Institute Bioscience, NR4 7UQ, Norwich, UK
| | - Naomi Knox
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Jillian Yong Xin Sieh
- School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK
| | - Marton Olbei
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
- Organisms and Ecosystems, Earlham Institute, NR4 7UZ, Norwich, UK
- Gut Microbes and Health Programme, Quadram Institute Bioscience, NR4 7UQ, Norwich, UK
| | - Zhigang Liu
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Hajir Ibraheim
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Jesus Miguens Blanco
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Hiromi Kudo
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Rocio Castro Seoane
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Lucia A Possamai
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Robert Goldin
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Julian Marchesi
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
| | - Tamas Korcsmaros
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
- Organisms and Ecosystems, Earlham Institute, NR4 7UZ, Norwich, UK
- Gut Microbes and Health Programme, Quadram Institute Bioscience, NR4 7UQ, Norwich, UK
| | - Graham M Lord
- School of Immunology and Microbial Sciences, King's College London, London, SE1 9RT, UK
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9NT, UK
| | - Nick Powell
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, W12 0NN, UK.
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36
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Middha P, Thummalapalli R, Betti MJ, Yao L, Quandt Z, Balaratnam K, Bejan CA, Cardenas E, Falcon CJ, Faleck DM, Gubens MA, Huntsman S, Johnson DB, Kachuri L, Khan K, Li M, Lovly CM, Murray MH, Patel D, Werking K, Xu Y, Zhan LJ, Balko JM, Liu G, Aldrich MC, Schoenfeld AJ, Ziv E. Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.05.15.23289680. [PMID: 37292751 PMCID: PMC10246037 DOI: 10.1101/2023.05.15.23289680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Immune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is a key to advancing precision immuno-oncology. Immune checkpoint inhibitor-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Based on clinical presentation, IMC mimics inflammatory bowel disease, however the link is poorly understood. We hypothesized that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) may predispose to IMC. We developed and validated polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer who received ICIs. Prevalence of all-grade IMC in our cohort was 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRSUC predicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76, P=0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35, P=0.01). PRSCD was not associated with IMC or severe IMC. The association between PRSUC and IMC (all-grade and severe) was consistent in an independent pan-cancer cohort of patients treated with ICIs. Furthermore, PRSUC predicted severe IMC among patients treated with combination ICIs (OR = 2.20 per SD, 95% CI = 1.07-4.53, P=0.03). This is the first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.
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Affiliation(s)
- Pooja Middha
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Rohit Thummalapalli
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael J Betti
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Lydia Yao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Zoe Quandt
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Diabetes Center, University of California San Francisco, San Francisco, CA, USA
| | | | - Cosmin A Bejan
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eduardo Cardenas
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Christina J Falcon
- Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David M Faleck
- Gastroenterology, Hepatology & Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Matthew A Gubens
- Medical Oncology, University of California San Francisco, San Francisco, CA, USA
- Department of Medicine, Weill Cornell Medical Center, New York, NY, USA
| | - Scott Huntsman
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Douglas B Johnson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Linda Kachuri
- Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA
- Stanford Cancer Institute, Stanford University of Medicine, Stanford, CA, USA
| | - Khaleeq Khan
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Min Li
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Christine M Lovly
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, TN, USA
| | - Megan H Murray
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Kristin Werking
- Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yaomin Xu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Luna Jia Zhan
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Justin M Balko
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Geoffrey Liu
- Princess Margaret Cancer Centre, Temerty School of Medicine, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Melinda C Aldrich
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Adam J Schoenfeld
- Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elad Ziv
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Helen Diller Family Comprehensive Cancer Center, Center for Genes, Environment and Health and Institute for Human Genetics, University of California San Francisco, San Francisco, California
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Machado AP, Ratliff H, Abdelwahab A, Vohra MH, Kuang A, Shatila M, Khan MA, Shafi MA, Thomas AS, Philpott J, Alhalabi O, Wang Y. The Safety of Immunosuppressants Used in the Treatment of Immune-Related Adverse Events due to Immune Checkpoint Inhibitors: a Systematic Review. J Cancer 2023; 14:2956-2963. [PMID: 37859810 PMCID: PMC10583582 DOI: 10.7150/jca.87335] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 08/30/2023] [Indexed: 10/21/2023] Open
Abstract
Purpose: Immune checkpoint inhibitor (ICI) use can lead to immune-related adverse events (irAEs) that require treatment with immunosuppressive medications in moderate to severe cases. Oncology society guidelines recommend systemic steroids and immunosuppressants such as infliximab and vedolizumab for the treatment of refractory cases. Limited information is available about the safety profile and potential adverse effects of these immunosuppressants. We have investigated the safety profile of multiple immunosuppressants which are used in the treatment of ICI-related irAEs. Methods: We performed a systematic review of studies reporting irAEs, from ICI use, and their medical management with immunosuppressants in adult cancer patients. We searched MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov from inception through September 1, 2022, using the following keywords or their equivalents: ICI, immunosuppressant, and irAE. We extracted observational studies and clinical trials that matched our criteria. A random effects model was used to estimate the overall incidence of infections associated with the treatment of irAEs. Results: Among the 11 studies included in this review (1036 total patients), melanoma (548 patients, 52.9%) was the most common primary cancer, followed by lung cancer (139 patients, 13.4%) and genitourinary cancers (131 patients, 12.6%). PD-1/PD-L1 monotherapy (460 patients, 44.4%) was used most, followed by a combination of PD-1/PD-L1 and CTLA-4 therapy (350 patients, 33.8%) and CTLA-4 monotherapy (226 patients, 22%). A total of 1024 (98.8%) patients had their irAEs treated with systemic steroids with majority having colitis and hepatobiliary irAEs; 335 patients (32.3%) were also treated with infliximab (mainly for colitis). Our review found 22.3% of patients treated for irAEs developed infectious adverse events (95% CI: 15.6%-29.1%, p<0.001). Among the 3 studies reporting the types of infections (41 total patients), bacterial (80.5%), followed by fungal (36.6%), infections were most common. Conclusions: Adverse events from irAE treatment occurred in about one-third of patients that received either steroids or a combination of steroids and other immunosuppressants. Clinicians should be aware of these immunosuppressant-related adverse effects, which can negatively impact cancer treatment and patient outcomes, when treating irAEs and consider shortening treatment duration or using alternative strategies when possible to mitigate these complications, future prospective studies should further investigate the safety of immunosuppressants in treating irAEs.
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Affiliation(s)
- Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Hunter Ratliff
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Ahmed Abdelwahab
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Muhammad H. Vohra
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Andrew Kuang
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Malek Shatila
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Muhammad Ali Khan
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Menhaz A. Shafi
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha S. Thomas
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jessica Philpott
- Inflammatory Bowel Disease Center, Cleveland Clinic, Cleveland, OH, USA
| | - Omar Alhalabi
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Dougan M. Gastrointestinal mucosal toxicities from immune checkpoint inhibitors: Current understanding and future directions. Immunol Rev 2023; 318:11-21. [PMID: 37455375 DOI: 10.1111/imr.13239] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 06/27/2023] [Indexed: 07/18/2023]
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized the field of oncology over the past decade, leading to durable remissions in some patients but also producing a wide spectrum of treatment-limiting inflammatory toxicities that are referred to as immune-related adverse events (irAEs). Although irAEs can involve any organ system in the body, they most commonly affect the barrier tissues, including the gastrointestinal tract with colitis and enterocolitis affecting a significant fraction of patients on ICIs. We are beginning to understand the mechanisms that drive ICI colitis, with early experiments indicating a role for CD8+ resident memory T cells (TRMs) in the gut, which become activated and differentiate into cytotoxic cells in response to ICI therapy. The risk factors that define who will develop ICI colitis are not understood and substantial efforts are underway to identify potential biomarkers for risk of this and other toxicities. Optimal management of ICI colitis is also an area of active investigation. Current standard treatments are based largely on small, retrospective analyses, and while drugs like systemic glucocorticoids or the TNFα inhibitor infliximab do appear to be highly active in ICI colitis, the impact of these therapies on antitumor responses is poorly understood. As discussed in this review, future work will have to define the immune mechanisms driving ICI colitis in more detail and in comparison to antitumor responses in order to identify candidate pathways that can be targeted to improve ICI colitis without interfering in antitumor immunity. Studying these interventions will require randomized, controlled trials with both tumor and colitis endpoints, a goal that will necessitate collaboration across institutions and funding agencies. We are at a point where such collaborative trials are feasible, and have the potential to greatly improve the care of patients with ICI colitis as well as other irAEs.
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Affiliation(s)
- Michael Dougan
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Li C, Wang L, Sun D, Yao T, Xian X, Cheng Y. Colitis induced by PD-1 inhibitor combined with platinum-containing dual drug chemotherapy in Lewis mice and its mechanism. J Cancer Res Ther 2023; 19:939-944. [PMID: 37675720 DOI: 10.4103/jcrt.jcrt_2078_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
Aims To explore the occurrence and possible mechanism of colitis in Lewis mice treated with PD-1 inhibitor combined with platinum-containing dual drug chemotherapy. Subjects and Methods A Lewis lung cancer model of C57BL/6 mice was established, randomly divided into the treatment group (group C, PD-1 inhibitor + Carboplatin (CARB) + Pemetrexed (PEM)) and model group (group B, normal saline), and a control group (group A, normal saline) was set up. Observe the changes in tumor-free weight, tumor volume, disease activity index (DAI), colon histopathology, identify serum interleukin (IL)-10, interferon (IFN)-γ, the expression of claudin-1, and occludin mRNA in the colon in each animals. Results Compared with group A, the tumor-free weight of mice in B decreased (P < 0.001), the content of IL-10 in serum increased (P < 0.01), the content of IFN-γ in serum decreased (P < 0.01). Compared with group B, the transplanted tumor volume in C was reduced (P < 0.05), DAI scores of D4 (P < 0.001), and D7 (P < 0.001) were increased, colonic histopathology analysis showed that colitis occurred, serum IL-10 content was decreased (P < 0.05), IFN-γ content was increased (P < 0.05), and the mRNA expression of claudin-1 (P < 0.05) and occludin (P < 0.05) was reduced. Conclusions This treatment can inhibit the growth of transplanted tumors but will cause colitis in Lewis mice. The impairment of intestinal barrier function following administration cause an imbalance in the expression of pro-inflammatory and anti-inflammatory factors in the colon, thus causing colitis.
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Affiliation(s)
- Chunhai Li
- Department of Radiology, The Qilu Hospital of Shandong University, Jinan Shandong, China
| | - Lixin Wang
- Department of School of Nursing and Rehabilitation, Shandong University, Jinan, Shandong, China
| | - Daqian Sun
- Department of Radiology, The Qilu Hospital of Shandong University, Jinan Shandong, China
| | - Tianxiao Yao
- Department of Radiology, The Qilu Hospital of Shandong University, Jinan Shandong, China
| | - Xiuying Xian
- Department of Interventional Department, Jinan Central Hospital, Jinan Shandong, China
| | - Yufeng Cheng
- Department of Radiotherapy, The Qilu Hospital of Shandong University, Jinan, Shandong, China
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Terrin M, Migliorisi G, Dal Buono A, Gabbiadini R, Mastrorocco E, Quadarella A, Repici A, Santoro A, Armuzzi A. Checkpoint Inhibitor-Induced Colitis: From Pathogenesis to Management. Int J Mol Sci 2023; 24:11504. [PMID: 37511260 PMCID: PMC10380448 DOI: 10.3390/ijms241411504] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 07/06/2023] [Accepted: 07/07/2023] [Indexed: 07/30/2023] Open
Abstract
The advent of immunotherapy, specifically of immune checkpoint inhibitors (ICIs), for the treatment of solid tumors has deeply transformed therapeutic algorithms in medical oncology. Approximately one-third of patients treated with ICIs may de velop immune-related adverse events, and the gastrointestinal tract is often affected by different grades of mucosal inflammation. Checkpoint inhibitors colitis (CIC) presents with watery or bloody diarrhea and, in the case of severe symptoms, requires ICIs discontinuation. The pathogenesis of CIC is multifactorial and still partially unknown: anti-tumor activity that collaterally effects the colonic tissue and the upregulation of specific systemic inflammatory pathways (i.e., CD8+ cytotoxic and CD4+ T lymphocytes) are mainly involved. Many questions remain regarding treatment timing and options, and biological treatment, especially with anti-TNF alpha, can be offered to these patients with the aim of rapidly resuming oncological therapies. CIC shares similar pathogenesis and aspects with inflammatory bowel disease (IBD) and the use of ICI in IBD patients is under evaluation. This review aims to summarize the pathogenetic mechanism underlying CIC and to discuss the current evidenced-based management options, including the role of biological therapy, emphasizing the relevant clinical impact on CIC and the need for prompt recognition and treatment.
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Affiliation(s)
- Maria Terrin
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Giulia Migliorisi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Arianna Dal Buono
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
| | - Roberto Gabbiadini
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
| | - Elisabetta Mastrorocco
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Alessandro Quadarella
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
| | - Alessandro Repici
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy
| | - Alessandro Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy; (M.T.); (G.M.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy
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Wang SJ, Dougan SK, Dougan M. Immune mechanisms of toxicity from checkpoint inhibitors. Trends Cancer 2023; 9:543-553. [PMID: 37117135 PMCID: PMC10330206 DOI: 10.1016/j.trecan.2023.04.002] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/03/2023] [Accepted: 04/06/2023] [Indexed: 04/30/2023]
Abstract
Immunotherapy has changed the treatment landscape for cancer over the past decade. Inhibitors of the immune checkpoint proteins cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and PD ligand 1 (PD-L1) can induce durable remissions in a subset of patients with metastatic disease. However, these treatments can be limited by inflammatory toxicities that can affect any organ system in the body and in some cases can be life threatening. Considerable progress has been made in understanding the drivers of these toxicities as well as effective management strategies. Further research into understanding the molecular and cellular mechanisms that drive toxicity will enable better prediction of toxicity and development of optimized therapies for these toxicities that avoid interfering with antitumor immunity. In this review, we discuss our current understanding of the inflammatory toxicities from immune checkpoint inhibitors (ICIs) and propose optimal treatment strategies for these toxicities.
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Affiliation(s)
- S Jennifer Wang
- Department of Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Stephanie K Dougan
- Department of Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
| | - Michael Dougan
- Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
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Desmedt V, Jauregui-Amezaga A, Fierens L, Aspeslagh S, Dekervel J, Wauters E, Peeters M, Sabino J, Crapé L, Somers M, Hoorens A, Dutré J, Lobatón T. Position statement on the management of the immune checkpoint inhibitor-induced colitis via multidisciplinary modified Delphi consensus. Eur J Cancer 2023; 187:36-57. [PMID: 37116287 DOI: 10.1016/j.ejca.2023.03.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 02/10/2023] [Accepted: 03/23/2023] [Indexed: 04/30/2023]
Abstract
INTRODUCTION The use of immune checkpoint inhibitors (ICIs) in cancer immunotherapy has shown increased overall survival in a wide range of cancer types with the associated risk of developing severe immune-mediated adverse events, commonly involving the gastrointestinal tract. AIM The aim of this position statement is to provide an updated practice advice to the gastroenterologists and oncologists on the diagnosis and management of ICI-induced gastrointestinal toxicity. METHODOLOGY The evidence reviewed in this paper includes a comprehensive search strategy of English language publications. Consensus was reached using a three-round modified Delphi methodology and approved by the members of the Belgian Inflammatory Bowel Disease Research and Development Group (BIRD), Belgian Society of Medical Oncology (BSMO), Belgian group of Digestive Oncology (BGDO), and Belgian Respiratory Society (BeRS). CONCLUSIONS The management of ICI-induced colitis requires an early multidisciplinary approach. A broad initial assessment is necessary (clinical presentation, laboratory markers, endoscopic and histologic examination) to confirm the diagnosis. Criteria for hospitalisation, management of ICIs, and initial endoscopic assessment are proposed. Even if corticosteroids are still considered the first-line therapy, biologics are recommended as an escalation therapy and as early treatment in patients with high-risk endoscopic findings.
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Affiliation(s)
- Valérie Desmedt
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Belgium
| | - Aranzazu Jauregui-Amezaga
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Belgium; Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium.
| | - Liselotte Fierens
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Catholic University of Leuven, Belgium
| | | | - Jeroen Dekervel
- Department of Gastroenterology and Hepatology, University Hospital Leuven, Belgium
| | - Els Wauters
- Respiratory Oncology Unit (Pulmonology), University Hospitals KU Leuven, Leuven, Belgium; Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Marc Peeters
- Department of Digestive Oncology, University Hospital Antwerp, Belgium
| | - Joao Sabino
- Department of Gastroenterology and Hepatology, University Hospital Leuven, Belgium
| | - Lara Crapé
- Department of Gastroenterology, Algemeen Stedelijk Ziekenhuis Aalst, Belgium
| | - Michael Somers
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Belgium
| | - Anne Hoorens
- Department of Pathology, University Hospital Ghent, Belgium
| | - Joris Dutré
- Department of Gastroenterology, Ziekenhuis Netwerk Antwerpen Jan Palfijn, Belgium
| | - Triana Lobatón
- Department of Gastroenterology and Hepatology, University Hospital Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
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Cheng Y, Ling F, Li J, Chen Y, Xu M, Li S, Zhu L. An updated review of gastrointestinal toxicity induced by PD-1 inhibitors: from mechanisms to management. Front Immunol 2023; 14:1190850. [PMID: 37404814 PMCID: PMC10315615 DOI: 10.3389/fimmu.2023.1190850] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/05/2023] [Indexed: 07/06/2023] Open
Abstract
PD-1 inhibitors, as one of commonly used immune checkpoint inhibitors, enable T-cell activation and prevent immune escape by blocking the PD-1/PD-L1 signaling pathway. They have transformed the treatment landscape for cancer in recent years, due to the advantages of significantly prolonging patients' survival and improving their life quality. However, the ensuing unpredictable immune-related adverse effects (irAEs) plague clinicians, such as colitis and even potentially fatal events like intestinal perforation and obstruction. Therefore, understanding the clinical manifestations and grading criteria, underlying mechanisms, available diverse therapies, accessible biomarkers, and basis for risk stratification is of great importance for the management. Current evidence suggests that irAEs may be a marker of clinical benefit to immunotherapy in patients, so whether to discontinue PD-1 inhibitors after the onset of irAEs and rechallenge after remission of irAEs requires further evaluation of potential risk-reward ratios as well as more data from large-scale prospective studies to fully validate. At the end, the rare gastrointestinal toxicity events caused by PD-1 inhibitors are also sorted out. This review provides a summary of available data on the gastrointestinal toxicity profile caused by PD-1 inhibitors, with the aim of raising clinicians' awareness in daily practice, so that patients can safely benefit from therapy.
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Badran YR, Zou F, Durbin SM, Dutra BE, Abu-Sbeih H, Thomas AS, Altan M, Thompson JA, Qiao W, Leet DE, Lai PY, Horick NK, Postow MA, Faleck DM, Wang Y, Dougan M. Concurrent immune checkpoint inhibition and selective immunosuppressive therapy in patients with immune-related enterocolitis. J Immunother Cancer 2023; 11:e007195. [PMID: 37349130 PMCID: PMC10314704 DOI: 10.1136/jitc-2023-007195] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2023] [Indexed: 06/24/2023] Open
Abstract
PURPOSE Immune checkpoint inhibitor (ICI) therapy is often suspended because of immune-related enterocolitis (irEC). We examined the effect of resumption of ICIs with or without concurrent selective immunosuppressive therapy (SIT) on rates of symptom recurrence and survival outcomes. METHODS This retrospective, multicenter study examined patients who were treated with ICI and developed irEC requiring SIT (infliximab or vedolizumab) for initial symptom control or to facilitate steroid tapering between May 2015 and June 2020. After symptom resolution, patients were restarted either on ICI alone or on concurrent ICI and SIT at the discretion of the treating physicians. The associations between irEC recurrence and treatment group were assessed via univariate analyses and multivariate logistic regression. Cox proportional hazards model was used for survival analysis. RESULTS Of the 138 included patients who required SIT for initial irEC symptom control, 61 (44.2%) patients resumed ICI without concurrent SIT (control group) and 77 (55.8%) patients resumed ICI therapy with concurrent SIT: 33 with infliximab and 44 with vedolizumab. After symptom resolution, patients in the control group were more commonly restarted on a different ICI regimen (65.6%) compared with those receiving SIT (31.2%) (p<0.001). The total number of ICI doses administered after irEC resolution and ICI resumption was similar in both groups (four to five doses). Recurrence of severe colitis or diarrhea after ICI resumption was seen in 34.4% of controls compared with 20.8% of patients receiving concurrent SIT. Concurrent SIT was associated with reduced risk of severe irEC recurrence after ICI resumption in a multivariate logistic regression model (OR 0.34; 95% CI 0.13 to 0.92; p=0.034). There was no difference in survival outcomes between patients in the control group and patients concurrently treated with SIT. CONCLUSION After resolution of irEC symptoms, reinitiation of ICI with concurrent SIT is safe, reduces severe irEC recurrence, and has no negative impact on survival outcomes.
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Affiliation(s)
- Yousef R Badran
- Division of Gastroenterology, Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, MA, USA
| | - Fangwen Zou
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Oncology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, People's Republic of China
| | - Sienna M Durbin
- Harvard Medical School, Boston, MA, USA
- Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Barbara E Dutra
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Hamzah Abu-Sbeih
- Department of Internal Medicine, University of Missouri Kansas City, Kansas City, Missouri, USA
| | - Anusha S Thomas
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mehmet Altan
- Department of Thoracic, Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - John A Thompson
- Department of Medicine, Division of Oncology, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, University of Washington, Seattle, Washington, USA
| | - Wei Qiao
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Donna E Leet
- Harvard Medical School, Boston, MA, USA
- Department of Internal Medicine, University of California San Francisco, San Francisco, California, USA
| | - Po-Ying Lai
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | - Nora K Horick
- Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
| | - Michael A Postow
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medicine, Weill Cornell Medical Center, New York, New York, USA
| | - David M Faleck
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Department of Medicine, Weill Cornell Medical Center, New York, New York, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michael Dougan
- Division of Gastroenterology, Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, MA, USA
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45
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Losurdo G, Angelillo D, Favia N, Sergi MC, Di Leo A, Triggiano G, Tucci M. Checkpoint Inhibitor-Induced Colitis: An Update. Biomedicines 2023; 11:biomedicines11051496. [PMID: 37239166 DOI: 10.3390/biomedicines11051496] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/17/2023] [Accepted: 05/19/2023] [Indexed: 05/28/2023] Open
Abstract
Immunotherapy with immune checkpoint inhibitors (ICIs) nowadays has indications for several solid tumors. The current targets for ICIs are CTLA-4, PD-1, and PD-L1 receptors. Despite the clinical advantages derived from ICIs, a variety of side effects are linked to overstimulation of the immune system. Among these, ICI-related colitis is one of the most common, with a disabling impact on the patient. Diarrhea, abdominal pain, abdominal distension, cramping, and hematochezia are the most common ICI enterocolitis presenting symptoms. The most frequently used grading system for assessment of the severity of ICI enterocolitis is called the Common Terminology Criteria for Adverse Events (CTCAE) grading. With regard to the histological picture, there is no specific feature; however, microscopic damage can be classified into five types: (1) acute active colitis, (2) chronic active colitis, (3) microscopic colitis-like, (4) graft-versus-host disease-like, and (5) other types. Supportive therapy (oral hydration, a bland diet without lactose or caffeine, and anti-diarrheal agents) is indicated in mild colitis. Symptomatic treatment alone or with loperamide, a low-fiber diet, and spasmolytics are recommended for low-grade diarrhea. In more severe cases, corticosteroid treatment is mandatory. In refractory cases, off-label use of biological therapies (infliximab or vedolizumab) was proposed.
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Affiliation(s)
- Giuseppe Losurdo
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Daniele Angelillo
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Nicolas Favia
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Maria Chiara Sergi
- Medical Oncology Unit, Azienda Ospedaliero Universitaria Policlinico di Bari, 70124 Bari, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari "Aldo Moro", 70124 Bari, Italy
| | - Giacomo Triggiano
- Medical Oncology Unit, Azienda Ospedaliero Universitaria Policlinico di Bari, 70124 Bari, Italy
| | - Marco Tucci
- Medical Oncology Unit, Azienda Ospedaliero Universitaria Policlinico di Bari, 70124 Bari, Italy
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", 70124 Bari, Italy
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46
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Verheijden RJ, van Eijs MJM, May AM, van Wijk F, Suijkerbuijk KPM. Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance. NPJ Precis Oncol 2023; 7:41. [PMID: 37173424 PMCID: PMC10182067 DOI: 10.1038/s41698-023-00380-1] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/18/2023] [Indexed: 05/15/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) have changed perspectives for patients with cancer, but come with severe immune-related adverse events (irAEs). To prevent fatality or chronicity, these irAEs are often promptly treated with high-dose immunosuppressants. Until recently, evidence on the effects of irAE management on ICI efficacy has been sparse. As a result, algorithms for irAE management are mostly expert-opinion based and barely consider possible detrimental effects of immunosuppressants on ICI efficacy. However, recent growing evidence suggests that vigorous immunosuppressive management of irAEs comes with unfavourable effects on ICI efficacy and survival. With expansion of the indications of ICIs, evidence-based treatment of irAEs without hampering tumour control becomes more and more important. In this review, we discuss novel evidence from pre-clinical and clinical studies on the effects of different irAE management regimens including corticosteroids, TNF inhibition and tocilizumab on cancer control and survival. We provide recommendations for pre-clinical research, cohort studies and clinical trials that can help clinicians in tailored irAE management, minimising patients' burden while maintaining ICI efficacy.
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Affiliation(s)
- Rik J Verheijden
- Department of Medical Oncology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
- Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
| | - Mick J M van Eijs
- Department of Medical Oncology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Anne M May
- Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Femke van Wijk
- Center for Translational Immunology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Karijn P M Suijkerbuijk
- Department of Medical Oncology, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
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47
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Malik A, Yousaf MN, Samiullah S, Tahan V, Mahdi A. Overlapping Hepatotoxicity and Colitis Associated with Immune Checkpoint Inhibitors. J Community Hosp Intern Med Perspect 2023; 13:75-78. [PMID: 37877043 PMCID: PMC10593176 DOI: 10.55729/2000-9666.1172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/26/2023] [Accepted: 01/27/2023] [Indexed: 10/26/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are widely used for the management of many solid-organ and hematologic cancers. These agents work by inhibition of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death-1 (PD-1), and PD ligand 1 (PD-L1). Hyperactivation of immune system results in ICI-associated adverse events. Simultaneous hepatotoxicity and colitis associated with ICIs is rare and potentially overlooked, as clinical symptoms are often nonspecific. A 73-year-old man with metastatic squamous cell carcinoma presented six weeks after starting pembrolizumab with abdominal discomfort and diarrhea. Pembrolizumab therapy was held, and supportive therapy with antidiarrheals provided partial relief. After initial workup, ICI-associated hepatitis (ICIH) and ICI-related colitis (ICIC) were diagnosed. Colitis resolution required corticosteroids. This case illustrates the importance of high index of clinical suspensions for gastrointestinal and hepatic adverse events associated with ICIs, which may be overlooked and result in severe complications. While isolated ICIH and ICIC are well known adverse events, overlapping ICIH and ICIC is rare. Prompt recognition, cessation of the inciting agent, and initiation of early supportive therapy are essential. Treatment may require corticosteroids or mycophenolate mofetil.
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Affiliation(s)
- Alexander Malik
- Department of Medicine, Summa Health System, Akron, OH,
United States
| | - Muhammad N. Yousaf
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO,
United States
| | - Sami Samiullah
- Department of Gastroenterology, Division of Advanced Endoscopy, Summa Health System, Akron, OH,
United States
| | - Veysel Tahan
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO,
United States
| | - Amin Mahdi
- Department of Gastroenterology, Division of Advanced Endoscopy, Summa Health System, Akron, OH,
United States
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48
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Immune Checkpoint Inhibitors in Breast Cancer: A Narrative Review. Oncol Ther 2023:10.1007/s40487-023-00224-9. [PMID: 36917399 DOI: 10.1007/s40487-023-00224-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 02/24/2023] [Indexed: 03/16/2023] Open
Abstract
Breast cancer is the most frequently diagnosed malignancy in patients worldwide and the main cause of cancer-related death. Though still incurable, metastatic breast cancer's prognosis has been considerably improved in the past 10 years due to the introduction of new targeted agents, such as immune checkpoint inhibitors (ICI). However, these medications are associated with unique side effects known as immune-mediated adverse events (irAE). In this paper, we review the clinical evidence for the use of ICIs in breast cancer, in both the metastatic as well as neoadjuvant/adjuvant setting, followed by a review of irAE most commonly seen, and the medications used to treat them. Our opinion is that any cancer specialist treating patients with breast cancer should be aware of these side effects for early detection and management, and oncologists should be the leaders of the multidisciplinary team that will take care of them.
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49
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Brongiel S, Rychalsky KL, Luon D, Johnson AR, Price C, Abdelghany O. Management of Steroid-Refractory Gastrointestinal Immune-Related Adverse Events. Ann Pharmacother 2023; 57:148-155. [PMID: 35656843 DOI: 10.1177/10600280221094330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) cause inflammatory immune-related adverse events (irAEs), which are often effectively managed with steroids. Less is known about the best management of irAEs refractory to steroid treatment. OBJECTIVE We aimed to assess the efficacy of second-line medications used to treat gastrointestinal (GI) irAEs. METHODS This study was a single-center, retrospective medical record review of patients who received steroids for an ICI GI irAE and at least one dose of infliximab, vedolizumab, or adalimumab for irAE treatment from March 25, 2011 to September 20, 2019, approved by Yale University's Institutional Review Board. Our primary objective was to assess the efficacy of second-line treatment, measured by the change in the Common Terminology Criteria for Adverse Events Version 5.0 grading system. RESULTS A total of 39 patients met inclusion criteria. Treatment for steroid-refractory GI irAEs demonstrated a high response rate, with irAE resolution seen in 89.7% of patients. Patients who were specifically initiated on infliximab within 14 days of starting steroids had a higher percent resolution seen in 94.4% of patients. The average time to response, defined as the average days from second-line therapy to reported symptom resolution, was 17 days. CONCLUSION AND RELEVANCE Steroid-refractory GI irAEs can be managed effectively in most patients with immunosuppressive therapy, such as infliximab. Furthermore, initiating second-line immunosuppressive therapy within 14 days of steroid failure resulted in a higher rate of symptom resolution.
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Affiliation(s)
- Samantha Brongiel
- Department of Pharmacy, Yale New Haven Health Smilow Cancer Hospital, New Haven, CT, USA
| | - Kristen L Rychalsky
- Department of Pharmacy, Yale New Haven Health Smilow Cancer Hospital, New Haven, CT, USA
| | - Darren Luon
- Department of Pharmacy, Yale New Haven Health Smilow Cancer Hospital, New Haven, CT, USA
| | - Aubrey R Johnson
- Department of Pharmacy, Massachusetts General Hospital, Boston, MA, USA
| | - Christina Price
- Yale School of Medicine, Department of Allergy and Immunology, New Haven, CT, USA
| | - Osama Abdelghany
- Department of Pharmacy, Yale New Haven Health Smilow Cancer Hospital, New Haven, CT, USA
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50
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Nicolaides S, Boussioutas A. Immune-Related Adverse Events of the Gastrointestinal System. Cancers (Basel) 2023; 15:cancers15030691. [PMID: 36765649 PMCID: PMC9913287 DOI: 10.3390/cancers15030691] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/19/2023] [Accepted: 01/21/2023] [Indexed: 01/24/2023] Open
Abstract
Immune checkpoint inhibitors (ICI) are a form of immunotherapy that have revolutionized the treatment of a number of cancers. Specifically, they are antibodies targeted against established and emerging immune checkpoints, such as cytotoxic T-cell antigen 4 (CTLA4), programmed cell death ligand 1 (PD-L1) and programmed cell death 1 protein (PD-1) on CD8-positive T cells, which promote the destruction of tumor cells. While the immune checkpoint inhibitors are very effective in the treatment of a number of cancers, their use is limited by serious and in some cases life-threatening immune-related adverse events. While these involve many organs, one of the most prevalent serious adverse events is immune checkpoint inhibitor colitis, occurring in a significant proportion of patients treated with this therapy. In this review, we aim to broadly describe the immune-related adverse events known to occur within the gastrointestinal system and the potential role played by the intestinal microbiome.
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Affiliation(s)
- Steven Nicolaides
- Department of Gastroenterology, Western Health, Melbourne, VIC 3011, Australia
- Department of Gastroenterology, The Alfred, Melbourne, VIC 3004, Australia
| | - Alex Boussioutas
- Department of Gastroenterology, The Alfred, Melbourne, VIC 3004, Australia
- Department of Medicine, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3050, Australia
- Correspondence:
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