|
1
|
Bell MG, Braga Neto MB, Kane SV. De Novo Crohn's Disease 3 Years Following Immune Checkpoint Inhibitor Therapy. ACG Case Rep J 2025; 12:e00944. [PMID: 40182190 PMCID: PMC11968015 DOI: 10.14309/crj.0000000000000944] [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: 07/01/2022] [Accepted: 11/28/2022] [Indexed: 04/05/2025] Open
Abstract
Presented is a 76-year-old man with metastatic melanoma that was successfully treated with pembrolizumab, an immune checkpoint inhibitor (ICI). He underwent 20 months of ICI treatment without dose limiting side effects. Nearly 18 months after ICI discontinuation, the patient developed intermittent epigastric pain and diarrhea. Owing to mild symptoms, he was not immediately evaluated. Three years after ICI cessation, he was diagnosed with stricturing, jejunal Crohn's disease. He was treated with vedolizumab and displayed clinical and radiographic response to treatment. This case serves as an example of potential gastrointestinal-related, long-term autoimmune implications of ICI therapy, even in patients without acute side effects.
Collapse
Affiliation(s)
- Matthew G. Bell
- Department of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ
| | | | - Sunanda V. Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| |
Collapse
|
|
2
|
Grimaldi C, Ibraghimov A, Kiessling A, Rattel B, Ji C, Fuller CL, Brennan FR, Regenass-Lechner F, Shenton J, Price KD, Piché MS, Steeves MA, Prell R, Dudal S, Kronenberg S, Freebern W, Blanset D. Current nonclinical approaches for immune assessments of immuno-oncology biotherapeutics. Drug Discov Today 2023; 28:103440. [PMID: 36375739 DOI: 10.1016/j.drudis.2022.103440] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/30/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022]
Abstract
Harnessing the immune system to kill tumors has been revolutionary and, as a result, has had an enormous benefit for patients in extending life and resulting in effective cures in some. However, activation of the immune system can come at the cost of undesirable adverse events such as cytokine release syndrome, immune-related adverse events, on-target/off-tumor toxicity, neurotoxicity and tumor lysis syndrome, which are safety risks that can be challenging to assess non-clinically. This article provides a review of the biology and mechanisms that can result in immune-mediated adverse effects and describes industry approaches using in vitro and in vivo models to aid in the nonclinical safety risk assessments for immune-oncology modalities. Challenges and limitations of knowledge and models are also discussed.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Sherri Dudal
- Roche Pharmaceutical Research and Early Development, United States
| | - Sven Kronenberg
- Roche Pharmaceutical Research and Early Development, United States
| | | | - Diann Blanset
- Boehringer Ingelheim Pharmaceuticals, Inc., United States.
| |
Collapse
|
|
3
|
Saha A, Dreyfuss I, Sarfraz H, Friedman M, Markowitz J. Dietary Considerations for Inflammatory Bowel Disease Are Useful for Treatment of Checkpoint Inhibitor-Induced Colitis. Cancers (Basel) 2022; 15:84. [PMID: 36612082 PMCID: PMC9817715 DOI: 10.3390/cancers15010084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.
Collapse
Affiliation(s)
- Aditi Saha
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Isabella Dreyfuss
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Humaira Sarfraz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Mark Friedman
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Joseph Markowitz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
- Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA
| |
Collapse
|
|
4
|
He H, Chen Q, Fan H, Leng XY, Zhu F, Gao F, Zhou Q, Dong Y, Yang J. Extracellular vesicles produced by bone marrow mesenchymal stem cells overexpressing programmed death-ligand 1 ameliorate dextran sodium sulfate-induced ulcerative colitis in rats by regulating Th17/Treg cell balance through PTEN/PI3K/AKT/mTOR axis. J Gastroenterol Hepatol 2022; 37:2243-2254. [PMID: 36044618 PMCID: PMC10087423 DOI: 10.1111/jgh.15987] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 08/07/2022] [Accepted: 08/22/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Programmed death-ligand 1 (PD-L1) was involved in regulating Th17/Treg cell balance in ulcerative colitis (UC). Extracellular vesicles (EVs) from genetically modified bone marrow mesenchymal stem cells (BMSCs) can serve as a stable delivery system to overexpress PD-L1. The study was designed to evaluate the therapeutic mechanism of BMSC-EVs overexpressing PD-L1 (PD-L1-EVs) on ulcerative colitis. METHODS Experimental model of UC was established in rats by drinking 5% dextran sulfate sodium (DSS). Apoptosis-related proteins, inflammatory response-related factors and oxidative stress related mediators were detected. Westernblot was used to detecte key proteins in the PI3K/AKT signaling pathway and its downstream effectors. The CD4+ Foxp3+ Treg cells and CD4+ IL-17A+ Th17 cells in spleen and mesenteric lymph nodes (MLNs) was detected by flow cytometry. RESULTS PD-L1-EVs significantly alleviated the manifestations and pathological damage of UC rats by inhibiting the expression of IFN-γ, IL-1β, IL-8, IL-6, IL-2, BAX, NF-κB, TNF-α, MPO, and MDA, and up-regulating the expression of IL-4, BCL-2, SOD, and GSH. Furthermore, the proportions of Th17 cells were decreased and that of Treg cells were upregulated by PD-L1-EVs treatment. PTEN inhibitors (bpv) partially abolished the inhibitory effect of PD-L1-EVs on PI3K-AKT signaling and impaired the therapeutic efficacy of PD-L1-EVs. CONCLUSIONS PD-L1-EVs mitigated colonal inflammation, apoptosis and oxidative stress through blocking the activation of PI3K/Akt/mTOR pathway and regulating the balance of Th17/Treg cells.
Collapse
Affiliation(s)
- Hongxia He
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qianyun Chen
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Heng Fan
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xue Yuan Leng
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Feng Zhu
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Fei Gao
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qiaoli Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yalan Dong
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jia Yang
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| |
Collapse
|
|
5
|
Ma C, MacDonald JK, Nguyen TM, Vande Casteele N, Linggi B, Lefevre P, Wang Y, Feagan BG, Jairath V. Pharmacological Interventions for the Prevention and Treatment of Immune Checkpoint Inhibitor-Associated Enterocolitis: A Systematic Review. Dig Dis Sci 2022; 67:1128-1155. [PMID: 33770330 DOI: 10.1007/s10620-021-06948-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/08/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Patients treated with immune checkpoint inhibitors (ICIs) may develop ICI-associated enterocolitis, for which there is no approved treatment. AIMS We aimed to systematically review the efficacy and safety of medical interventions for the prevention and treatment of ICI-associated enterocolitis. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched to identify randomized controlled trials (RCTs), cohort and case-control studies, and case series/reports, evaluating interventions (including corticosteroids, biologics, aminosalicylates, immunosuppressants, and fecal transplantation) for ICI-associated enterocolitis. Clinical, endoscopic, and histologic efficacy endpoints were evaluated. The Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to assess overall quality of evidence. RESULTS A total of 160 studies (n = 1514) were included (one RCT, 3 retrospective cohort studies, 156 case reports/case series). Very low quality evidence from one RCT suggests budesonide is not effective for prevention of ICI-associated enterocolitis in ipilimumab-treated patients (relative risk 0.93 [95% confidence interval 0.56, 1.56]). Very low quality evidence suggests that corticosteroids, infliximab, and vedolizumab may be effective for treatment of ICI-associated enterocolitis by inducing clinical response and remission. No validated indices for measuring disease activity were used. Biologic treatment was used in 42% (641/1528) of patients, as reported in 97 studies. ICIs were discontinued in 65% (457/702) of patients, as reported in 63 studies. CONCLUSIONS Current treatment recommendations for ICI-associated enterocolitis are based on very low quality evidence, primarily from case reports and case series. Large-scale prospective cohort studies and RCTs are needed to develop prophylactic and therapeutic treatments to minimize interruption or discontinuation of oncological therapies.
Collapse
Affiliation(s)
- Christopher Ma
- Division of Gastroenterology and Hepatology, Departments of Medicine and Community Health Sciences, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada.
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada.
| | - John K MacDonald
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
| | - Tran M Nguyen
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
| | - Niels Vande Casteele
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
- Division of Gastroenterology, University of California San Diego, 4350 Executive Drive, Suite 210, La Jolla, San Diego, CA, 92121, USA
| | - Bryan Linggi
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
| | - Pavine Lefevre
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA
| | - Brian G Feagan
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
- Departments of Medicine, Epidemiology, and Biostatistics, Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada
| | - Vipul Jairath
- Alimentiv Inc (Formerly Robarts Clinical Trials), 100 Dundas St, Suite #200, London, ON, N6A 5B6, Canada
- Departments of Medicine, Epidemiology, and Biostatistics, Western University, 1151 Richmond St, London, ON, N6A 3K7, Canada
| |
Collapse
|
|
6
|
Kikuchi H, Sakuraba H, Akemoto Y, Hosoi K, Murai Y, Hoshi K, Fukutoku Y, Asari T, Sawada Y, Hasui K, Tatsuta T, Hiraga H, Chinda D, Mikami T, Fukuda S. Endoscopic and histopathologic features of Anti‐PD‐1‐related collagenous colitis. DEN OPEN 2022; 2:e92. [PMID: 35310729 PMCID: PMC8828179 DOI: 10.1002/deo2.92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 12/01/2021] [Accepted: 12/25/2021] [Indexed: 11/22/2022]
Abstract
Objectives Cancer patients treated with immune checkpoint inhibitors occasionally show persistent diarrhea accompanied by endoscopic features of ulcerative colitis. The endoscopic mucosal inflammation may appear mild in some patients compared to the clinical severity, which can make choosing a treatment challenging. In this study, we evaluated the factors that support the continuation of chemotherapy by assessing the endoscopic and histopathological characteristics of patients who experienced diarrhea after immune checkpoint inhibitor administration. Methods This study included eight patients who were diagnosed with collagenous colitis based on pathological assessments. We retrospectively investigated these patients’ backgrounds, laboratory data, and computed tomography images that were extracted from their medical records. We also summarized their endoscopic and pathologic findings. Results All eight patients were being treated with anti‐programmed cell death‐1/programmed cell death‐ligand 1 therapeutic agents and had a recent history of oral proton pump inhibitor therapy. The anti‐programmed cell death‐1‐related collagenous colitis in these cases was characterized by endoscopically mild mucosal inflammation, high fecal calprotectin levels, and a lower frequency of intestinal wall thickening on computed tomography. Histological assessments showed CD8+ lymphocytes predominantly infiltrating the lamina propria and crypts of the colonic mucosa. Suspending the proton pump inhibitor therapy relieved the patients’ symptoms and allowed the continuation of the anti‐programmed cell death‐1/programmed cell death‐ligand 1 therapy. Conclusions Anti‐programmed cell death‐1‐related collagenous colitis is reversible; appropriate diagnosis of adverse events is crucial for the continuation of immune checkpoint inhibitor therapy.
Collapse
Affiliation(s)
- Hidezumi Kikuchi
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
- Department of Community Medicine Hirosaki University Graduate School of Medicine Aomori Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Yui Akemoto
- Department of Anatomic Pathology Hirosaki University Hospital Aomori Japan
| | - Kazuhiro Hosoi
- Department of Pharmacy Hirosaki University Hospital Aomori Japan
| | - Yasuhisa Murai
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Kentaro Hoshi
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Yukari Fukutoku
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Taka Asari
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Yohei Sawada
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Keisuke Hasui
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Tetsuya Tatsuta
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Hiroto Hiraga
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Daisuke Chinda
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| | - Tatsuya Mikami
- Innovation Center for Health Promotion Hirosaki University Graduate School of Medicine Aomori Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology and Hematology Hirosaki University Graduate School of Medicine Aomori Japan
| |
Collapse
|
|
7
|
Del Sordo R, Lougaris V, Bassotti G, Armuzzi A, Villanacci V. Therapeutic agents affecting the immune system and drug-induced inflammatory bowel disease (IBD): A review on etiological and pathogenetic aspects. Clin Immunol 2022; 234:108916. [PMID: 34971840 DOI: 10.1016/j.clim.2021.108916] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 01/02/2023]
Abstract
In recent years, therapeutic agents affecting the immune system have been largely implemented in the treatment of various hematological, rheumatological and dermatological disorders. Their clinical use has offered important benefits for affected patients and has also ameliorated clinical outcome and prognosis in many cases. Nonetheless, as any treatment, the use of these drugs may be associated with side effects. One of the target organs in such cases is the gastrointestinal tract. In particular, the exacerbation or the onset of inflammatory bowel disease (IBD) in treated patients is not infrequent, although the mechanism of action of these agents may be different. In this review we will focus on the use of therapeutic agents affecting the immune system and the development or exacerbation of IBD, with a mention on the possible underlying pathogenetic mechanisms.
Collapse
Affiliation(s)
- Rachele Del Sordo
- Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy
| | - Vassilios Lougaris
- Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia and Children's Hospital, ASST-Spedali Civili, Brescia, Italy..
| | - Gabrio Bassotti
- Gastroenterology & Hepatology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessandro Armuzzi
- IBD Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | | |
Collapse
|
|
8
|
Khan J, Katona T. Immune Checkpoint Inhibitor-Induced Colitis Presenting As Lymphocytic Colitis. Cureus 2021; 13:e18085. [PMID: 34692300 PMCID: PMC8523195 DOI: 10.7759/cureus.18085] [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] [Accepted: 09/18/2021] [Indexed: 11/15/2022] Open
Abstract
Checkpoint inhibitors (CPIs) are a new class of drugs that have changed the treatment and prognosis of several malignancies, even in their advanced stages. These drugs have increased patient survival rates. CPIs stimulate the immune system and include cytotoxic T-lymphocyte antigen-4 inhibitors (ipilimumab), programmed cell death inhibitors such as pembrolizumab, nivolumab, and avelumab, and programmed cell death protein ligand-1 inhibitors such as atezolizumab. Herein, we present a case of CPI-induced colitis in a 45-year-old woman with a history of melanoma. The melanoma was BRAF-positive with a V600 mutation. She had metastasis to the brain and the right 10th rib, which underwent surgery and radiation treatment, respectively. She was treated with nivolumab and denosumab. The patient presented with chronic watery diarrhea. Biopsy revealed lymphocytic colitis-like changes in the colon and terminal ileum. Thus, given the history of CPIs, a diagnosis of CPIS-induced colitis was made.
Collapse
Affiliation(s)
- Jaffar Khan
- Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, USA
| | - Terrence Katona
- Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, USA
| |
Collapse
|
|
9
|
Freitas AP, Clissa PB, Soto DR, Câmara NOS, Faquim-Mauro EL. The modulatory effect of crotoxin and its phospholipase A 2 subunit from Crotalus durissus terrificus venom on dendritic cells interferes with the generation of effector CD4 + T lymphocytes. Immunol Lett 2021; 240:56-70. [PMID: 34626682 DOI: 10.1016/j.imlet.2021.09.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 09/30/2021] [Accepted: 09/30/2021] [Indexed: 01/02/2023]
Abstract
Dendritic Cells (DCs) direct either cellular immune response or tolerance. The crotoxin (CTX) and its CB subunit (phospholipase A2) isolated from Crotalus durissus terrificus rattlesnake venom modulate the DC maturation induced by a TLR4 agonist. Here, we analyzed the potential effect of CTX and CB subunit on the functional ability of DCs to induce anti-ovalbumin (OVA) immune response. Thus, CTX and CB inhibited the maturation of OVA/LPS-stimulated BM-DCs from BALB/c mice, which means inhibition of costimulatory and MHC-II molecule expression and proinflammatory cytokine secretion, accompanied by high expression of ICOSL, PD-L1/2, IL-10 and TGF-β mRNA expression. The addition of CTX and CB in cultures of BM-DCs incubated with ConA or OVA/LPS inhibited the proliferation of CD3+ or CD4+T cells from OVA-immunized mice. In in vitro experiment of co-cultures of purified CD4+T cells of DO11.10 mice with OVA/LPS-stimulated BM-DCs, the CTX or CB induced lowest percentage of Th1 and Th2 and CTX induced increase of Treg cells. In in vivo, CTX and CB induced lower percentage of CD4+IFNγ+ and CD4+IL-4+ cells, as well as promoted CD4+CD25+IL-10+ population in OVA/LPS-immunized mice. CTX in vivo also inhibited the maturation of DCs. Our findings demonstrate that the modulatory action of CTX and CB on DCs interferes with the generation of adaptive immunity and, therefore contribute for the understanding of the mechanisms involved in the generation of cellular immunity, which can be useful for new therapeutic approaches for immune disorders.
Collapse
Affiliation(s)
- Amanda P Freitas
- Laboratory of Immunopathology, Butantan Institute, São Paulo, SP, Brazil; Department of Immunology, Institute of Biomedical Science, University of São Paulo, SP, Brazil
| | - Patricia B Clissa
- Laboratory of Immunopathology, Butantan Institute, São Paulo, SP, Brazil
| | - Dunia R Soto
- Laboratory of Biotechnology, Butantan Institute, São Paulo, Brazil
| | - Niels O S Câmara
- Department of Immunology, Institute of Biomedical Science, University of São Paulo, SP, Brazil
| | - Eliana L Faquim-Mauro
- Laboratory of Immunopathology, Butantan Institute, São Paulo, SP, Brazil; Department of Immunology, Institute of Biomedical Science, University of São Paulo, SP, Brazil.
| |
Collapse
|
|
10
|
Isidro RA, Ruan AB, Gannarapu S, Raj D, Rahma O, Grover S, Srivastava A. Medication-specific variations in morphological patterns of injury in immune check-point inhibitor-associated colitis. Histopathology 2020; 78:532-541. [PMID: 32931028 DOI: 10.1111/his.14248] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 09/08/2020] [Indexed: 12/16/2022]
Abstract
AIMS A varied spectrum of histopathological changes has been associated with immune checkpoint inhibitor (ICI) colitis. This study was performed to evaluate the prevalence of different histopathological patterns of injury in patients with ICI colitis and their association with specific immune check-point inhibitors. METHODS AND RESULTS Biopsies from patients with clinically and histologically confirmed ICI colitis were reviewed blindly to determine the predominant pattern of injury and to quantitate discrete histological parameters using the Geboes score. Paneth cell metaplasia, intraepithelial lymphocytes, abnormal subepithelial collagen and degree of crypt epithelial apoptosis was also recorded. A total of 86 patients with ICI colitis (ipilimumab, n = 14; ipilimumab + nivolumab, n = 29; nivolumab, n = 20 and pembrolizumab, n = 23) were included. The patterns of injury identified included diffuse active colitis (n = 22), chronic active colitis (n = 22), lymphocytic colitis (LC, n = 16), collagenous colitis (CC, n = 14), graft-versus-host disease-like colitis (n = 7) and mixed colitis (n = 5). Patients on ipilimumab were more likely to have a diffuse active colitis pattern without features of chronicity (P < 0.01) and less likely to have LC (P < 0.05) compared to other ICIs. LC and CC were more common in patients on nivolumab and pembrolizumab relative to other groups (P < 0.05). Chronic active colitis was most frequent in nivolumab patients (P < 0.05), and these patients had received more ICI doses and had been on ICI treatment longer compared to other treatment groups. CONCLUSIONS ICI colitis should be considered in the differential diagnosis of all the common inflammatory patterns of colitis and shows medication specific differences in patterns of injury.
Collapse
Affiliation(s)
- Raymond A Isidro
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Swetha Gannarapu
- Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA
| | - Dhanya Raj
- Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA
| | - Osama Rahma
- Division of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Shilpa Grover
- Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA, USA
| | - Amitabh Srivastava
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
11
|
Ibraheim H, Baillie S, Samaan MA, Abu-Sbeih H, Wang Y, Talley NJ, P Jones M, Powell N. Systematic review with meta-analysis: effectiveness of anti-inflammatory therapy in immune checkpoint inhibitor-induced enterocolitis. Aliment Pharmacol Ther 2020; 52:1432-1452. [PMID: 32920854 DOI: 10.1111/apt.15998] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 03/29/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Immune checkpoint inhibitors have revolutionised cancer treatment, but at the cost of off-target immune-mediated organ damage. This includes checkpoint inhibitor-induced enterocolitis which frequently requires hospitalisation and may be life-threatening. Empiric treatment typically includes corticosteroids and infliximab, although no large-scale studies have confirmed their effectiveness. AIM To investigate the effectiveness of anti-inflammatory therapy in checkpoint inhibitor-induced enterocolitis METHODS: We performed a systematic review and meta-analysis of studies reporting clinical outcomes of checkpoint inhibitor-induced enterocolitis in adult cancer patients treated with anti-inflammatory agents. We searched Medline, EMBASE, and the Cochrane library through April and extracted the proportion of patients responding to anti-inflammatory therapy. Variation in effect size was studied using a random-effects meta-regression analysis, with checkpoint inhibitor agent and tumour type as the variables. RESULTS Data were pooled from 1210 treated patients across 39 studies. Corticosteroids were effective in 59% (95% CI 54- 65) of patients, with response significantly more favourable in patients treated with anti-PD-1/L1 monotherapy, compared with anti-CTLA-4 containing regimens (78%, 95% CI 69-85 vs 56 %, 95% CI 49-63, P = 0.003), and more favourable in lung cancer patients compared with melanoma patients (88%, 95% CI 62-97 vs 55%, 95% CI 47-63, P = 0.04). Infliximab was effective in 81% (95% CI 73-87) of patients, and vedolizumab in 85% (95% CI 60-96). CONCLUSION Corticosteroids, infliximab and vedolizumab, are effective in the treatment of checkpoint inhibitor-induced enterocolitis. Checkpoint inhibitor regimen and cancer type were significant moderators in response to corticosteroid therapy.
Collapse
Affiliation(s)
- Hajir Ibraheim
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK.,The Royal Marsden Hospital, London, UK
| | | | - Mark A Samaan
- Department of Gastroenterology, Guy's and St Thomas' Hospital, London, UK
| | | | - Yinghong Wang
- The University of Texas MD Anderson Cancer Cente, Houston, TX, USA
| | | | - Michael P Jones
- Psychology Department, Macquarie University, North Ryde, NSW, Australia
| | - Nick Powell
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, UK.,The Royal Marsden Hospital, London, UK
| |
Collapse
|
|
12
|
Moore M, Feakins RM, Lauwers GY. Non-neoplastic colorectal disease biopsies: evaluation and differential diagnosis. J Clin Pathol 2020; 73:783-792. [PMID: 32737191 DOI: 10.1136/jclinpath-2020-206794] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Accepted: 05/30/2020] [Indexed: 12/11/2022]
Abstract
A wide variety of non-neoplastic conditions may be encountered on colorectal biopsy encompassing idiopathic, infectious, vascular and immune-mediated aetiologies. Although interpretation of such biopsies may be challenging, appreciation of the dominant pattern of injury and subsequent host response may allow for a more focused histological diagnosis in the correct clinical and endoscopic setting. This article aims to provide a systematic, methodical approach to the assessment of such biopsies, concentrating mainly on diagnoses other than inflammatory bowel disease.
Collapse
Affiliation(s)
- Michelle Moore
- Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK
| | | | | |
Collapse
|
|
13
|
Powell N, Ibraheim H, Raine T, Speight RA, Papa S, Brain O, Green M, Samaan MA, Spain L, Yousaf N, Hunter N, Eldridge L, Pavlidis P, Irving P, Hayee B, Turajlic S, Larkin J, Lindsay JO, Gore M. British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis. Lancet Gastroenterol Hepatol 2020; 5:679-697. [PMID: 32553146 DOI: 10.1016/s2468-1253(20)30014-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 01/21/2020] [Accepted: 01/21/2020] [Indexed: 12/15/2022]
Abstract
Immune checkpoint inhibitors are a novel class of cancer treatment that have improved outcomes for a subset of cancer patients. They work by antagonising inhibitory immune pathways, thereby augmenting immune-mediated antitumour responses. However, immune activation is not cancer-specific and often results in the activation of immune cells in non-cancer tissues, resulting in off-target immune-mediated injury and organ dysfunction. Diarrhoea and gastrointestinal tract inflammation are common and sometimes serious side-effects of this type of therapy. Prompt recognition of gastrointestinal toxicity and, in many cases, rapid institution of anti-inflammatory or biologic therapy (or both) is required to reverse these complications. Management of organ-specific complications benefits from multidisciplinary input, including engagement with gastroenterologists for optimal management of immune checkpoint inhibitor-induced enterocolitis. In this British Society of Gastroenterology endorsed guidance document, we have developed a consensus framework for the investigation and management of immune checkpoint inhibitor-induced enterocolitis.
Collapse
MESH Headings
- Adrenal Cortex Hormones/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/toxicity
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/toxicity
- Consensus
- Endoscopy/methods
- Endoscopy, Digestive System/methods
- Enterocolitis/chemically induced
- Enterocolitis/drug therapy
- Enterocolitis/metabolism
- Gastroenterology/organization & administration
- Gastrointestinal Diseases/chemically induced
- Gastrointestinal Diseases/diagnostic imaging
- Gastrointestinal Diseases/pathology
- Guidelines as Topic
- Humans
- Infliximab/therapeutic use
- Lactoferrin/metabolism
- Leukocyte L1 Antigen Complex/metabolism
- Neoplasms/drug therapy
- Patient Care Management/methods
- Societies, Medical/organization & administration
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- United Kingdom/epidemiology
Collapse
Affiliation(s)
- Nick Powell
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, UK; The Royal Marsden Hospital, London, UK.
| | - Hajir Ibraheim
- Division of Digestive Diseases, Faculty of Medicine, Imperial College London, UK; The Royal Marsden Hospital, London, UK
| | - Tim Raine
- Addenbrooke's Hospital, Cambridge University Teaching Hospitals NHS Foundation Trust, Cambridge, UK
| | - Richard A Speight
- Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK; Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Sophie Papa
- School of Cancer and Pharmaceutical Sciences, King's College London, London, UK; Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Oliver Brain
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, UK
| | - Michael Green
- Department of Histopathology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Mark A Samaan
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | | | | | | | - Polychronis Pavlidis
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK; Centre for Inflammation and Cancer Immunology, King's College London, London, UK
| | - Peter Irving
- Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Bu'Hussain Hayee
- Department of Gastroenterology, King's College Hospital, London, UK
| | - Samra Turajlic
- The Royal Marsden Hospital, London, UK; Cancer Dynamics Laboratory, The Francis Crick Institute, London, UK
| | | | - James O Lindsay
- The Royal London Hospital, Barts Health NHS Trust, London, UK; Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | | |
Collapse
|
|
14
|
Grover S, Dougan M, Tyan K, Giobbie-Hurder A, Blum SM, Ishizuka J, Qazi T, Elias R, Vora KB, Ruan AB, Martin-Doyle W, Manos M, Eastman L, Davis M, Gargano M, Haq R, Buchbinder EI, Sullivan RJ, Ott PA, Hodi FS, Rahma OE. Vitamin D intake is associated with decreased risk of immune checkpoint inhibitor-induced colitis. Cancer 2020; 126:3758-3767. [PMID: 32567084 DOI: 10.1002/cncr.32966] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/24/2020] [Accepted: 04/27/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND There is a lack of predictive markers informing on the risk of colitis in patients treated with immune checkpoint inhibitors (ICIs). The aim of this study was to identify potential factors associated with development of ICI colitis. METHODS We performed a retrospective analysis of melanoma patients at Dana-Farber Cancer Institute who received PD-1, CTLA-4, or combination ICIs between May 2011 to October 2017. Clinical and laboratory characteristics associated with pathologically confirmed ICI colitis were evaluated using multivariable logistic regression analyses. External confirmation was performed on an independent cohort from Massachusetts General Hospital. RESULTS The discovery cohort included 213 patients of whom 37 developed ICI colitis (17%). Vitamin D use was recorded in 66/213 patients (31%) before starting ICIs. In multivariable regression analysis, vitamin D use conferred significantly reduced odds of developing ICI colitis (OR 0.35, 95% CI 0.1-0.9). These results were also demonstrated in the confirmatory cohort (OR 0.46, 95% CI 0.2-0.9) of 169 patients of whom 49 developed ICI colitis (29%). Pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≥5 predicted reduced odds of colitis (OR 0.34, 95% CI 0.1-0.9) only in the discovery cohort. CONCLUSIONS This is the first study to report that among patients treated with ICIs, vitamin D intake is associated with reduced risk for ICI colitis. This finding is consistent with prior reports of prophylactic use of vitamin D in ulcerative colitis and graft-versus-host-disease. This observation should be validated prospectively in future studies.
Collapse
Affiliation(s)
- Shilpa Grover
- Harvard Medical School, Boston, Massachusetts.,Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael Dougan
- Harvard Medical School, Boston, Massachusetts.,Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Kevin Tyan
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Anita Giobbie-Hurder
- Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Steven M Blum
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Broad Institute at MIT and Harvard, Cambridge, Massachusetts.,Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Jeffrey Ishizuka
- Departments of Medicine and Pathology, Yale University School of Medicine, New Haven, Connecticut
| | - Taha Qazi
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.,Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Rawad Elias
- Hartford HealthCare Cancer Institute, Hartford, Connecticut
| | | | - Alex B Ruan
- Harvard Medical School, Boston, Massachusetts
| | - William Martin-Doyle
- Harvard Medical School, Boston, Massachusetts.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael Manos
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Lauren Eastman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Meredith Davis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Maria Gargano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Rizwan Haq
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Elizabeth I Buchbinder
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Ryan J Sullivan
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | - Patrick A Ott
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.,Broad Institute at MIT and Harvard, Cambridge, Massachusetts.,Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - F Stephen Hodi
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Osama E Rahma
- Harvard Medical School, Boston, Massachusetts.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| |
Collapse
|
|
15
|
Abu Khalaf S, Albarrak A, Yousef M, Tahan V. Immune checkpoint inhibitors induced colitis, stay vigilant: A case report. World J Gastrointest Oncol 2020; 12:699-704. [PMID: 32699584 PMCID: PMC7340999 DOI: 10.4251/wjgo.v12.i6.699] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/07/2020] [Accepted: 05/19/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Colitis is one of the immune-related side effects of immunotherapy. Usually, such type of side effect was reported to develop within a few weeks of treatment initiation, our case started within a few days. CASE SUMMARY We present a case of a 37-year-old gentleman with bright red loose stools, abdominal pain, and tenesmus. A diagnosis of colitis was made based on endoscopic and histologic findings. Treatment was thereafter continued with oral steroids and discontinuation of the immunotherapy medications. Symptoms resolved after starting the treatment and the patient continued to be symptom-free on subsequent follow-up. The unique about this case report is that the patient developed bloody diarrhea within five days of the 1st immunotherapy cycle, and the patient was on combined ipilimumab and nivolumab. CONCLUSION Immunotherapy related complications might occur within days from being on immunotherapy; we need more research to open the way for future pathological and clinical research to further understand the pathophysiology behind it.
Collapse
Affiliation(s)
- Suha Abu Khalaf
- Department of Internal Medicine, University of Missouri, Columbia, MO 65212, United States
| | - Abdulmajeed Albarrak
- Department of Internal Medicine, College of Medicine, Qassim University, Buraydah 81999, Saudi Arabia
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| | - Mohamad Yousef
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| | - Veysel Tahan
- Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, United States
| |
Collapse
|
|
16
|
Johncilla M, Grover S, Zhang X, Jain D, Srivastava A. Morphological spectrum of immune check-point inhibitor therapy-associated gastritis. Histopathology 2020; 76:531-539. [PMID: 31692018 DOI: 10.1111/his.14029] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023]
Abstract
AIMS Immune check-point inhibitors are frequently used in the treatment of a variety of solid tumours. The mechanism of action of these drugs involves up-regulation of cytotoxic T cells, which can lead to a lack of self-tolerance and immune-related adverse events, including those involving the gastrointestinal tract. This study was performed to characterise the histological features of immune check-point inhibitor therapy-associated gastritis. METHODS AND RESULTS Gastric biopsies from patients on immune check-point inhibitor therapy with clinical suspicion of drug-associated gastrointestinal injury were identified. The predominant histological pattern of injury, distribution of injury, degree of tissue eosinophilia and prominence of apoptosis were recorded. Presenting symptoms, treatment and follow-up data were obtained by medical chart review. The 12 patients included in the study group were treated with ipilimumab, nivolumab or pembrolizumab for a variety of tumours. Symptoms at presentation included nausea, vomiting and diarrhoea. Chronic active gastritis with intra-epithelial lymphocytosis and prominent apoptosis was seen in eight of 12 patients, and was the most useful combination for the diagnosis of drug-induced gastritis in these patients. Four patients showed focal enhancing gastritis with a lymphohistiocytic cuff around inflamed glands reminiscent of Crohn's disease. One of those four patients was homozygous for the ATG16L1 Crohn's disease-associated gene variant, but had no history of inflammatory bowel disease. Ten patients responded to medication withdrawal and steroid therapy, while two required treatment with infliximab. CONCLUSIONS Awareness of the morphological spectrum of immune check-point inhibitor therapy-associated gastritis is important for the accurate diagnosis and prompt management of these patients.
Collapse
Affiliation(s)
- Melanie Johncilla
- Department of Pathology, Weill Cornell College of Medicine, New York, NY, USA
| | - Shilpa Grover
- Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Amitabh Srivastava
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
17
|
Abstract
Immune checkpoint inhibitors have revolutionized treatment and overall survival for several different types of cancer. Antibodies to cytotoxic T-lymphocyte-associated protein 4 and to programmed cell death protein 1 and its ligand enhance cytotoxic T-cell survival, thus augmenting antitumor action and consequently inducing immune-related adverse events, of which the most relevant is diarrhea and colitis. This review compiles recent data on pathophysiology, clinical manifestations, and treatment of immune-mediated colitis (IMC). The pathogenesis of IMC is not completely understood, but recent studies have focused on the role of regulatory T cells and interactions with the gut microbiome. While sharing similarities with inflammatory bowel disease, IMC is considered a distinct form of colitis with acute onset and rapid progression leading to potential complications including bowel perforation and death. Prompt recognition and management of IMC is imperative for optimal outcomes. Although prospective clinical trials are lacking to guide therapy, recent guidelines recommend early endoscopic evaluation to establish the diagnosis and prompt initiation of corticosteroids. Response to first-line therapy should be assessed early to determine the need of escalation to biologic agents. With treatment, most patients will experience full resolution of symptoms, and subsequent rechallenge with anti-programmed cell death protein 1 or anti-programmed death-ligand 1 inhibitors can be considered.
Collapse
|
|
18
|
Kostine M, Marabelle A, Schaeverbeke T, Kfoury M. [Toxicities of immune checkpoint inhibitors and their management]. Med Sci (Paris) 2020; 35:949-956. [PMID: 31903899 DOI: 10.1051/medsci/2019191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Immunotherapeutic strategies, notably immune checkpoint inhibitors, have become a standard of care for the treatment of advanced cancers, with a growing spectrum of activity. These monoclonal antibodies target the co-inhibitory signals between tumor cells or antigen-presenting cells and T cells, thereby enhancing antitumour T cell activity. However, the occurrence of immune-related adverse events, that can affect all organ-system, represents a major limiting factor to the clinical development of these antibodies. Management of such toxicity requires a close collaboration between oncologists and organ-specialists, by using glucocorticoids and/or other immunosuppressive therapies, with the common objective not alter anti-tumor response.
Collapse
Affiliation(s)
- Marie Kostine
- Service de rhumatologie, hôpital Pellegrin, Bordeaux, France
| | | | | | | |
Collapse
|
|
19
|
Chen E, Abu-Sbeih H, Thirumurthi S, Mallepally N, Khurana S, Wei D, Altan M, Morris VK, Tan D, Barcenas CH, Wang Y. Clinical characteristics of colitis induced by taxane-based chemotherapy. Ann Gastroenterol 2019; 33:59-67. [PMID: 31892799 PMCID: PMC6928479 DOI: 10.20524/aog.2019.0431] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 10/07/2019] [Indexed: 12/18/2022] Open
Abstract
Background: Limited data are available concerning the clinical features of toxic gastrointestinal (GI) effects of taxane-based therapy. We describe the clinical, endoscopic and histologic features of taxane-induced colitis. Methods: This retrospective study included cancer patients who received taxane therapy and underwent colonoscopy for GI symptoms from 2000-2018. Results: Of the 45,527 patients who received taxane therapy during the study period, 76 (0.2%) met the inclusion criteria. Most patients (54%) received paclitaxel, 37% docetaxel, and 9% nab-paclitaxel. The median time from taxane therapy initiation to colitis symptom onset was 31 days. The median duration of colitis symptoms was 30 days. Colitis treatment comprised immunosuppressive therapy in 8 patients (11%), antibiotics in 17 (22%), antimotility agents in 18 (24%), and octreotide or somatostatin in 2 (3%). Thirty-five patients (46%) required hospitalization and seven (9%) required admission to the intensive care unit (ICU). Endoscopy revealed mucosal ulceration in 19 patients (25%), nonulcerative inflammation in 32 (42%), and normal findings in 25 (33%). Seventeen patients (22%) had features of lymphocytic colitis. One patient had spontaneous colonic perforation that required surgical intervention. Colitis symptoms recurred in 7 patients (9%) after initial improvement. Patients who received nab-paclitaxel developed GI toxicity earlier (P=0.003), required colitis-related hospitalization more frequently (P=0.005), and received intravenous fluids more frequently (P=0.025), compared with patients who received other taxanes. Conclusions: Taxane-related colitis can present with significant inflammation on colonoscopy, and in a minority of patients as microscopic colitis. Taxane-induced colitis, although uncommon, can lead to ICU admission and colonic perforation.
Collapse
Affiliation(s)
- Ellie Chen
- Department of Medicine, Baylor College of Medicine (Ellie Chen, Niharika Mallepally)
| | - Hamzah Abu-Sbeih
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center (Hamzah Abu-Sbeih, Selvi Thirumurthi, Yinghong Wang)
| | - Selvi Thirumurthi
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center (Hamzah Abu-Sbeih, Selvi Thirumurthi, Yinghong Wang)
| | - Niharika Mallepally
- Department of Medicine, Baylor College of Medicine (Ellie Chen, Niharika Mallepally)
| | - Shruti Khurana
- Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center (Shruti Khurana)
| | - Dongguang Wei
- Department of Pathology and Lab Medicine, The University of Texas MD Anderson Cancer Center (Dongguang Wei, Dongfeng Tan)
| | - Mehmet Altan
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson, Cancer Center (Mehmet Altan)
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center (Van K. Morris)
| | - Dongfeng Tan
- Department of Pathology and Lab Medicine, The University of Texas MD Anderson Cancer Center (Dongguang Wei, Dongfeng Tan)
| | - Carlos H Barcenas
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center (Carlos H. Barcenas), Houston, Texas, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center (Hamzah Abu-Sbeih, Selvi Thirumurthi, Yinghong Wang)
| |
Collapse
|
|
20
|
Garo LP, Ajay AK, Fujiwara M, Beynon V, Kuhn C, Gabriely G, Sadhukan S, Raheja R, Rubino S, Weiner HL, Murugaiyan G. Smad7 Controls Immunoregulatory PDL2/1-PD1 Signaling in Intestinal Inflammation and Autoimmunity. Cell Rep 2019; 28:3353-3366.e5. [PMID: 31553906 PMCID: PMC6925592 DOI: 10.1016/j.celrep.2019.07.065] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 06/09/2019] [Accepted: 07/18/2019] [Indexed: 02/08/2023] Open
Abstract
Smad7, a negative regulator of TGF-β signaling, has been implicated in the pathogenesis and treatment of inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). Here, we found that Smad7 mediates intestinal inflammation by limiting the PDL2/1-PD1 axis in dendritic cells (DCs) and CD4+T cells. Smad7 deficiency in DCs promotes TGF-β responsiveness and the co-inhibitory molecules PDL2/1 on DCs, and it further imprints T cell-PD1 signaling to promote Treg differentiation. DC-specific Smad7 deletion mitigates DSS-induced colitis by inducing CD103+PDL2/1+DCs and Tregs. In addition, Smad7 deficiency in CD4+T cells promotes PD1 and PD1-induced Tregs in vitro. The transfer of Smad7-deficient CD4+T cells enhances Tregs in vivo and protects against T cell-mediated colitis. Furthermore, Smad7 antisense ameliorates DSS-induced UC, increasing TGF-β and PDL2/1-PD1 signaling. Enhancing PD1 signaling directly via Fc-fused PDL2/1 is also beneficial. Our results identify how Smad7 mediates intestinal inflammation and leverages these pathways therapeutically, providing additional strategies for IBD intervention.
Collapse
Affiliation(s)
- Lucien P Garo
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Amrendra K Ajay
- Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Mai Fujiwara
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Vanessa Beynon
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Chantal Kuhn
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Galina Gabriely
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Supriya Sadhukan
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Radhika Raheja
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Stephen Rubino
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Howard L Weiner
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Gopal Murugaiyan
- Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
| |
Collapse
|
|
21
|
Abstract
Checkpoint inhibitors (CI) have revolutionized the management of many cancers but can result in immune-related adverse events (IRAE). In this chapter, we review the clinical manifestations and management of the most common IRAE, plus less common IRAE, such as inflammatory arthritis, of particular interest to rheumatologists. We review the mechanism of action of CI, predictors of IRAE, and the impact of IRAE on cancer outcomes. The study of IRAE is in its infancy; there are very few prospective studies and virtually no treatment trials. Where possible, we have drawn estimates of IRAE incidence from meta-analyses of randomized controlled trials. Clinical descriptions are derived from case series and case reports. Readers are encouraged to refer to consensus guidelines for IRAE management published by the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer.
Collapse
|
|
22
|
Visekruna A, Hartmann S, Sillke YR, Glauben R, Fischer F, Raifer H, Mollenkopf H, Bertrams W, Schmeck B, Klein M, Pagenstecher A, Lohoff M, Jacob R, Pabst O, Bland PW, Luu M, Romero R, Siegmund B, Rajalingam K, Steinhoff U. Intestinal development and homeostasis require activation and apoptosis of diet-reactive T cells. J Clin Invest 2019; 129:1972-1983. [PMID: 30939122 DOI: 10.1172/jci98929] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 02/19/2019] [Indexed: 12/30/2022] Open
Abstract
The impact of food antigens on intestinal homeostasis and immune function is poorly understood. Here, we explored the impact of dietary antigens on the phenotype and fate of intestinal T cells. Physiological uptake of dietary proteins generated a highly activated CD44+Helios+CD4+ T cell population predominantly in Peyer patches. These cells are distinct from regulatory T cells and develop independently of the microbiota. Alimentation with a protein-free, elemental diet led to an atrophic small intestine with low numbers of activated T cells, including Tfh cells and decreased amounts of intestinal IgA and IL-10. Food-activated CD44+Helios+CD4+ T cells in the Peyer patches are controlled by the immune checkpoint molecule PD-1. Blocking the PD-1 pathway rescued these T cells from apoptosis and triggered proinflammatory cytokine production, which in IL-10-deficient mice was associated with intestinal inflammation. In support of these findings, our study of patients with Crohn's disease revealed significantly reduced frequencies of apoptotic CD4+ T cells in Peyer patches as compared with healthy controls. These results suggest that apoptosis of diet-activated T cells is a hallmark of the healthy intestine.
Collapse
Affiliation(s)
- Alexander Visekruna
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Sabrina Hartmann
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Yasmina Rodriguez Sillke
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Germany
| | - Rainer Glauben
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Germany
| | - Florence Fischer
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Hartmann Raifer
- Flow Cytometry Core Facility, Philipps University Marburg, Germany
| | - Hans Mollenkopf
- Max Planck Institute for Infection Biology, Core Facility Microarray/Genomics, Berlin, Germany
| | - Wilhelm Bertrams
- Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Philipps University Marburg, Germany
| | - Bernd Schmeck
- Institute for Lung Research, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Philipps University Marburg, Germany
| | - Matthias Klein
- Institute for Immunology, University Medical Center, Mainz, Germany
| | - Axel Pagenstecher
- Department of Neuropathology, Philipps University of Marburg, Germany
| | - Michael Lohoff
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Ralf Jacob
- Department of Cell Biology and Cell Pathology, Philipps University of Marburg, Germany
| | - Oliver Pabst
- Institute of Molecular Medicine, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
| | - Paul William Bland
- Department of Microbiology & Immunology, Gothenburg University, Gothenburg, Sweden
| | - Maik Luu
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Rossana Romero
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| | - Britta Siegmund
- Medical Department for Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Germany
| | | | - Ulrich Steinhoff
- Institute for Medical Microbiology and Hospital Hygiene, Philipps University of Marburg, Germany
| |
Collapse
|
|
23
|
Bajwa R, Cheema A, Khan T, Amirpour A, Paul A, Chaughtai S, Patel S, Patel T, Bramson J, Gupta V, Levitt M, Asif A, Hossain MA. Adverse Effects of Immune Checkpoint Inhibitors (Programmed Death-1 Inhibitors and Cytotoxic T-Lymphocyte-Associated Protein-4 Inhibitors): Results of a Retrospective Study. J Clin Med Res 2019; 11:225-236. [PMID: 30937112 PMCID: PMC6436564 DOI: 10.14740/jocmr3750] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 02/13/2019] [Indexed: 12/11/2022] Open
Abstract
In recent years the use of immunomodulating therapy to treat various cancers has been on the rise. Three checkpoint inhibitors have been approved by the Food and Drug Administration (ipilimumab, pembrolizumab and nivolumab). The use of these drugs comes with serious adverse events related to excessive immune activation, collectively known as immune-related adverse events (irAEs). We conducted a system-based review of 139 case reports/case series that have described these adverse events between January 2016 and April 2018, found in the PubMed database. There was a broad spectrum of presentations, doses and checkpoint inhibitors used. The most common check point inhibitor observed in our literature review was nivolumab. The most common adverse effects encountered were colitis (14/139), hepatitis (11/139), adrenocorticotropic hormone insufficiency (12/139), hypothyroidism (7/139), type 1 diabetes (22/139), acute kidney injury (16/139) and myocarditis (10/139). The treatment most commonly consisted of cessation of the immune checkpoint inhibitor, initiation of steroids and supportive therapy. This approach provided a complete resolution in a majority of cases; however, there were many that developed long-term adverse events with deaths reported in a few cases. The endocrine system was the mostly commonly affected with the development of type 1 diabetes mellitus or diabetic ketoacidosis being the most frequently reported adverse events. While immunomodulating therapy is a significant advance in the management of various malignancies, it is capable of serious adverse effects. Because the majority of the cases developed pancreatic dysfunction within five cycles of therapy, in addition to the evaluation of other systems, pancreatic function should be closely monitored to minimize adverse impact on patients.
Collapse
Affiliation(s)
- Ravneet Bajwa
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Anmol Cheema
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Taimoor Khan
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Alireza Amirpour
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Anju Paul
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Saira Chaughtai
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Shrinil Patel
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Tejas Patel
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Joshua Bramson
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Varsha Gupta
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Michael Levitt
- Department of Hematology/Oncology, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Arif Asif
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| | - Mohammad A Hossain
- Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA
| |
Collapse
|
|
24
|
Smith SCL, Zardo D, Cannatelli R, Stevens N, Iacucci M. Endoscopic findings of checkpoint inhibitor-induced ileitis with use of the latest advanced endoscopic optical diagnosis: near-focus narrow-band imaging. VideoGIE 2019; 4:133-135. [PMID: 30899894 PMCID: PMC6408926 DOI: 10.1016/j.vgie.2018.11.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Samuel C L Smith
- Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - Davide Zardo
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Rosanna Cannatelli
- Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - Neil Stevens
- University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Marietta Iacucci
- Institute of Translational Medicine, University of Birmingham, Birmingham, UK.,NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| |
Collapse
|
|
25
|
Fuchs S, Sawas N, Staedler N, Schubert DA, D'Andrea A, Zeiser R, Piali L, Hruz P, Frei AP. High-dimensional single-cell proteomics analysis identifies immune checkpoint signatures and therapeutic targets in ulcerative colitis. Eur J Immunol 2019; 49:462-475. [PMID: 30578679 DOI: 10.1002/eji.201847862] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 11/26/2018] [Accepted: 12/20/2018] [Indexed: 12/12/2022]
Abstract
Immune checkpoints are regulators of immune cells and play key roles in the modulation of immune responses. The role of checkpoints in autoimmune disease is poorly understood but likely to be central since checkpoint inhibition during cancer treatment can cause autoimmunity. We generated a high-dimensional single-cell proteomics data set from PBMCs of healthy individuals and patients with ulcerative colitis (UC) by mass cytometry, enabling systems-wide analyses of immune cell frequencies and cell type-specific expression patterns of 12 immune checkpoints. Subtle but significant changes in immune cell frequencies and checkpoint expression were observed between UC patients on different treatment regimens and between patients and healthy controls. Most strikingly, UC patients showed a reduced number of peripheral NK-cells and those cells showed an altered phenotype including increased TIGIT expression. Based on these results, we modulated NK-cell function ex vivo through targeting of TIGIT pathway members. In summary, we describe a pattern of changes in immune cell abundance and checkpoint expression as a basis for UC patient stratification and we show modulation of a corresponding immune cell subset through checkpoint targeting. Our approach can be used for the identification of pathogenic immune cell subsets and guide target selection in autoimmunity and chronic inflammation.
Collapse
Affiliation(s)
- Sebastian Fuchs
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
| | - Nadia Sawas
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
| | - Nicolas Staedler
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, BiOmics, Roche Innovation Center Basel, Basel, Switzerland
| | - David A Schubert
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
| | - Annalisa D'Andrea
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
| | - Robert Zeiser
- Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Luca Piali
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
| | - Petr Hruz
- Department of Gastroenterology, University Hospital, Basel, Switzerland
| | - Andreas P Frei
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
| |
Collapse
|
|
26
|
Ahmed M. Checkpoint inhibitors: What gastroenterologists need to know. World J Gastroenterol 2018; 24:5433-5438. [PMID: 30622372 PMCID: PMC6319137 DOI: 10.3748/wjg.v24.i48.5433] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/07/2018] [Accepted: 11/16/2018] [Indexed: 02/06/2023] Open
Abstract
Checkpoint inhibitors are increasingly being used in clinical practice. They can cause various gastrointestinal, hepatic and pancreatic side effects. As these side effects can be serious, appropriate management is essential. The different checkpoint inhibitors with their mechanisms of action and indications, as well as evaluation and management of gastrointestinal, hepatic and pancreatic side effects, are discussed in this article.
Collapse
Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
| |
Collapse
|
|
27
|
Esfahani K. Taking the bull by the horn: the frontline use of infliximab for the treatment of immune checkpoint inhibitor-induced enterocolitis. J Immunother Cancer 2018; 6:154. [PMID: 30577825 PMCID: PMC6303842 DOI: 10.1186/s40425-018-0480-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 12/11/2018] [Indexed: 02/08/2023] Open
Abstract
Immune checkpoint inhibitors which activate the host’s immune system to fight cancer have brought dramatic improvements to the overall survival of a growing number of deadly malignancies. Their use comes at the expense of often serious immune-related adverse events which consist of an off-target attack of the immune system on potentially any of the human body’s healthy organs. For lack of better-validated evidence, and regardless of the organ affected, clinicians often use the same immunosuppressive regimens consisting of high dose corticosteroids followed by the introduction of biologic agents such as the tumor-necrosis alpha inhibitor infliximab for corticosteroid-refractory toxicities. The article by Johnson et al. is timely in providing a more personalized approach for the management of immune-related toxicities affecting the lower digestive tract with many positive clinical outcomes associated with the upfront use of infliximab in association with corticosteroids. This commentary will provide a narrative summary of their findings in light of the current clinical knowledge relevant to the understanding of immune-related enterocolitis.
Collapse
Affiliation(s)
- Khashayar Esfahani
- Department of Medical Oncology, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, Canada.
| |
Collapse
|
|
28
|
Soularue E, Lepage P, Colombel JF, Coutzac C, Faleck D, Marthey L, Collins M, Chaput N, Robert C, Carbonnel F. Enterocolitis due to immune checkpoint inhibitors: a systematic review. Gut 2018; 67:2056-2067. [PMID: 30131322 DOI: 10.1136/gutjnl-2018-316948] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 07/11/2018] [Accepted: 07/19/2018] [Indexed: 12/14/2022]
Abstract
Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD-1)/ligand are increasingly used to treat several types of cancer. These drugs enhance antitumour T-cell activity and therefore induce immune-related adverse effects (irAE), of which gastrointestinal (GI) irAE are among the most frequent and severe. This systematic literature review summarises the clinical manifestations, management and pathophysiology of GI irAE due to immune checkpoint inhibitors. GI irAE induced by anti-CTLA-4 are frequent, potentially severe and resemble IBD, whereas those induced by PD-1 blockade seem to be less frequent and clinically more diverse. Baseline symbiotic gut microbiota is associated with an enhanced antitumour response to immune checkpoint inhibitors and an increased susceptibility to developing enterocolitis, in patients treated with anti-CTLA-4. These findings open new perspectives for possible manipulation of the gut microbiota in order to better identify responders to immune checkpoint inhibitors and to increase their efficacy and safety.
Collapse
Affiliation(s)
- Emilie Soularue
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.,Faculté de Médecine, University Paris-Saclay, Le Kremlin Bicêtre, France
| | - Patricia Lepage
- Micalis Institute, INRA, AgroParisTech, University Paris-Saclay, Jouy-en- Josas, France
| | - Jean Frederic Colombel
- Helmsley Inflammatory Bowel Disease Center, Icahn Medical School of Medicine at Mount Sinai, New York, USA
| | - Clelia Coutzac
- Laboratory of Immunomonitoring in Oncology and CNRS-UMS 3655 and INSERM-US23, Villejuif, France
| | - David Faleck
- Helmsley Inflammatory Bowel Disease Center, Icahn Medical School of Medicine at Mount Sinai, New York, USA
| | - Lysiane Marthey
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France
| | - Michael Collins
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.,Faculté de Médecine, University Paris-Saclay, Le Kremlin Bicêtre, France
| | - Nathalie Chaput
- Laboratory of Immunomonitoring in Oncology and CNRS-UMS 3655 and INSERM-US23, Villejuif, France.,Faculté de Pharmacie, University Paris-Saclay, Chatenay-Malabry, France
| | - Caroline Robert
- Faculté de Médecine, University Paris-Saclay, Le Kremlin Bicêtre, France.,Départment of Medecine, Dermatology Unit, Villejuif, France
| | - Franck Carbonnel
- Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.,Faculté de Médecine, University Paris-Saclay, Le Kremlin Bicêtre, France
| |
Collapse
|
|
29
|
Hamamoto Y, Shin N, Hoshino T, Kanai T. Management of challenging immune-related gastrointestinal adverse events associated with immune checkpoint inhibitors. Future Oncol 2018; 14:3187-3198. [PMID: 30188189 DOI: 10.2217/fon-2018-0509] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Immune-related gastrointestinal toxicities (irGI) are well-known adverse events (AEs) with immune checkpoint inhibitors. The aim of this review was to present clinical data from 82 cases to provide information to clinicians who face real-world challenges among their patients with irGI AEs. The findings of this review support the use of the current management guidelines. By analyzing the treatment courses and outcomes of all cases identified, our review recommends that recurrent cases be treated carefully regardless of the grade of diarrhea at the onset of events. Earlier gastroenterology consultation and computed tomography/endoscopy diagnosis are essential, especially when an irGI AE recurs or worsens during steroid tapering. We would also suggest earlier decision to add immunosuppressant agents, particularly for recurrent cases.
Collapse
Affiliation(s)
- Yasuo Hamamoto
- Keio Cancer Center, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Natalya Shin
- Research and Development Department, Division of Pharmacovigilance, Bristol-Myers Squibb K.K., Shinjuku-ku, Tokyo, Japan
| | - Tomohiro Hoshino
- Safety Strategy 2, Safety management, Division of Pharmacovigilance, Ono Pharmaceutical Co., Ltd, Chuo-ku, Osaka, Japan
| | - Takanori Kanai
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| |
Collapse
|
|
30
|
Guaitoli G, Baldessari C, Tomasello C, Barbieri F, Cascinu S, Bertolini F, Cesinaro AM. Late Gastrointestinal Toxicity During Nivolumab Therapy in Non-Small Cell Lung Cancer: A Rare Case of Inflammatory Bowel Disease. J Thorac Oncol 2018; 13:e152-e153. [PMID: 30049380 DOI: 10.1016/j.jtho.2018.03.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 03/26/2018] [Accepted: 03/27/2018] [Indexed: 01/02/2023]
Affiliation(s)
- Giorgia Guaitoli
- Department of Oncology and Haematology, Modena University Hospital, Modena, Italy.
| | - Cinzia Baldessari
- Department of Oncology and Haematology, Modena University Hospital, Modena, Italy
| | - Chiara Tomasello
- Department of Oncology and Haematology, Modena University Hospital, Modena, Italy
| | - Fausto Barbieri
- Department of Oncology and Haematology, Modena University Hospital, Modena, Italy
| | - Stefano Cascinu
- Department of Oncology and Haematology, Modena University Hospital, Modena, Italy
| | - Federica Bertolini
- Department of Oncology and Haematology, Modena University Hospital, Modena, Italy
| | | |
Collapse
|
|
31
|
Beswick EJ, Grim C, Singh A, Aguirre JE, Tafoya M, Qiu S, Rogler G, McKee R, Samedi V, Ma TY, Reyes VE, Powell DW, Pinchuk IV. Expression of Programmed Death-Ligand 1 by Human Colonic CD90 + Stromal Cells Differs Between Ulcerative Colitis and Crohn's Disease and Determines Their Capacity to Suppress Th1 Cells. Front Immunol 2018; 9:1125. [PMID: 29910803 PMCID: PMC5992387 DOI: 10.3389/fimmu.2018.01125] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 05/03/2018] [Indexed: 12/14/2022] Open
Abstract
Background and Aims The role of programmed cell death protein 1 (PD-1) and its ligands in the dysregulation of T helper immune responses observed in the inflammatory bowel disease (IBD) is unclear. Recently, a novel concept emerged that CD90+ colonic (myo)fibroblasts (CMFs), also known as stromal cells, act as immunosuppressors, and are among the key regulators of acute and chronic inflammation. The objective of this study was to determine if the level of the PD-1 ligands is changed in the IBD inflamed colonic mucosa and to test the hypothesis that changes in IBD-CMF-mediated PD-1 ligand-linked immunosuppression is a mechanism promoting the dysregulation of Th1 cell responses. Methods Tissues and cells derived from Crohn's disease (CD), ulcerative colitis (UC), and healthy individuals (N) were studied in situ, ex vivo, and in culture. Results A significant increase in programmed death-ligand 1 (PD-L1) was observed in the inflamed UC colonic mucosa when compared to the non-inflamed matched tissue samples, CD, and healthy controls. UC-CMFs were among the major populations in the colonic mucosa contributing to the enhanced PD-L1 expression. In contrast, PD-L1 expression was decreased in CD-CMFs. When compared to CD-CMFs and N-CMFs, UC-CMFs demonstrated stronger suppression of IL-2, Th1 transcriptional factor Tbet, and IFN-γ expression by CD3/CD28-activated CD4+ T cells, and this process was PD-L1 dependent. Similar observations were made when differentiated Th1 cells were cocultured with UC-CMFs. In contrast, CD-CMFs showed reduced capacity to suppress Th1 cell activity and addition of recombinant PD-L1 Fc to CD-CMF:T cell cocultures partially restored the suppression of the Th1 type responses. Conclusion We present evidence showing that increased PD-L1 expression suppresses Th1 cell activity in UC. In contrast, loss of PD-L1 expression observed in CD contributes to the persistence of the Th1 inflammatory milieu in CD. Our data suggest that dysregulation of the Th1 responses in the inflamed colonic mucosa of IBD patients is promoted by the alterations in PD-L1 expression in the mucosal mesenchymal stromal cell compartment.
Collapse
Affiliation(s)
- Ellen J Beswick
- Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM, United States
| | - Carl Grim
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States
| | - Abinav Singh
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States
| | - Jose E Aguirre
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States
| | - Marissa Tafoya
- Department of Pathology, University of New Mexico, Albuquerque, NM, United States
| | - Suimin Qiu
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital of Zürich, Zürich, Switzerland
| | - Rohini McKee
- Department of Surgery, University of New Mexico, Albuquerque, NM, United States
| | - Von Samedi
- Department of Pathology, University of New Mexico, Albuquerque, NM, United States
| | - Thomas Y Ma
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, NM, United States
| | - Victor E Reyes
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.,Department of Pediatrics, University of Texas Medical Branch, Galveston, TX, United States
| | - Don W Powell
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States
| | - Irina V Pinchuk
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States.,Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
| |
Collapse
|