Immune Checkpoint Inhibitor-induced Colitis Research Articles

Potential application mechanism of traditional Chinese medicine in treating immune checkpoint inhibitor-induced colitis.

Cancer ranks among the foremost causes of mortality worldwide, posing a significant threat to human lives. The advent of tumor immunotherapy has substantially transformed the therapeutic landscape for numerous advanced malignancies, notably non-small cell lung cancer and melanoma. However, as immune checkpoint inhibitors (ICIs) are increasingly applied in clinical settings, a spectrum of undesired reactions, termed immune-related adverse events (irAEs), has emerged. These adverse reactions are associated with immunotherapy and can result in varying degrees of harm to the human body. Among these reactions, Immune checkpoint inhibitor-induced colitis (ICIIC) stands out as one of the most prevalent clinical adverse events. In contemporary times, traditional Chinese medicine (TCM) has demonstrated remarkable efficacy in addressing various maladies. Consequently, investigating the potential application and mechanisms of Chinese medicine in countering immune checkpoint inhibitor-induced colitis assumes significant importance in the treatment of this condition.

Dysfunctional intestinal microvascular endothelial cells: Insights and therapeutic implications in gastrointestinal inflammation.

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.

Anti-integrin αvβ6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis

BackgroundNo specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvβ6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis.MethodsSerum anti-integrin αvβ6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvβ6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients.ResultsAnti-integrin αvβ6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvβ6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvβ6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvβ6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvβ6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC.ConclusionsAnti-integrin αvβ6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

The JAK-STAT Pathway as a Therapeutic Strategy in Cancer Patients with Immune Checkpoint Inhibitor-Induced Colitis: A Narrative Review

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.

P122 Digital spatial profiling reveals the predictive characteristics in patients with immune checkpoint inhibitor-induced colitis

Abstract Background The increasing use of immune checkpoint inhibitors (ICIs) against cancers is inevitably accompanied with immune-related adverse events (irAEs), and irAE colitis is one of the common types. The overactivation of CD8+ T cells plays a central role in irAEs. However, the local mechanisms related to irAE colitis remain unclear. Hence, we aimed to explore the transcriptional characteristics related to CD8+ T cell responses of irAE colitis. Methods Colon biopsy samples were collected from 6 irAE colitis patients and 5 non-irAE controls after ICIs treatment. Leveraging digital spatial profiling, 23 regions of interest (ROI) enriched with CD8+ T cells were selected and divided into 3 groups, which were non-irAE, pre-treatment irAE and post-treatment irAE. Differentially expressed genes (DEGs), protein-protein interaction (PPI) and weighted gene co-expression network analysis (WGCNA) were performed to identify the hub genes, and they were further verified by external single-cell RNA-seq data. Also, the immune infiltration analysis was performed (Figure 1A). Results Principal component analysis (PCA) indicated similar distribution among the 3 groups (Figure 1B). The comparisons of non-irAE vs. pre-treatment irAE, and pre-treatment irAE vs. post-treatment irAE yielded 105 and 210 DEGs respectively. WGCNA resulted in 14 clustering modules, with MEturquoise and MEmagenta exhibiting the highest correlation scores (Figure 1C). Importantly, 174 key genes were identified and prominently associated with various mitochondrial processes e.g. oxidative phosphorylation (Figure 1D). PPI analysis revealed a sub-module consisting of 22 nodes in MCODE. Further overlap analysis of CytoHubba and DEGs pinpointed 9 hub genes. Remarkably, COX5B was found at the intersection of both groups (Figure 1E). External single-cell RNA-seq data verified that all the hub genes were significantly highly expressed in the irAE colitis group except COX6A1 (Figure 1F). Besides, immune infiltration analyses revealed the higher levels of endothelial cells (P = 0.043) and fibroblasts (P &amp;lt;0.01) by SpatialDecon, and activated dendritic cells (P &amp;lt;0.001) by xCell in pre-treatment irAE, compared to non-irAE (Figure 1G). Further, immune cells correlation analysis demonstrated highly similar patterns of endothelial cells, fibroblasts, pDCs, and macrophages (Figure 1H). Conclusion COX5B related to mitochondrial processes characterized irAE colitis. Expansion of dendritic cells and stromal compartments including endothelial cells and fibroblasts may contribute to irAE development.

A role for the gut microbiota in immune checkpoint inhibitor-induced colitis.

A role for the gut microbiota in immune checkpoint inhibitor-induced colitis.

Immune checkpoint inhibitor-induced colitis with endoscopic evaluation in Chinese cancer patients: a single-centre retrospective study

BackgroundWe investigated the clinical and endoscopic features, management strategies, and outcomes of Chinese cancer patients with immune checkpoint inhibitor (ICI)-induced colitis.MethodThis single-centre retrospective study included patients who developed ICI-induced colitis and underwent endoscopic evaluation from June 1, 2019 to October 1, 2023. We analysed clinical features, ICI-induced colitis-related information, management strategies, and outcomes.ResultsA total of 25 patients were included; most were male (88%) with a median age of 59 years. Eleven (44%) patients had grade 2 colitis, and 14 (56%) had grade 3 colitis. The median time from ICI initiation to colitis onset was 105 days. The median duration from symptom onset to endoscopic evaluation was 11 days. Regarding endoscopic evaluation, colitis involved the entire colon in 13 (52%) patients, and 15 (60%) had ulcers. Twenty-three (92%) patients received steroids, and 3 (12%) added infliximab (IFX). Most patients (n=19, 76%) achieved remission with complete tapering of the steroid taken for the first colitis episode. Among the 6 (24%) patients who did not taper initial, 5 patients increased their steroid dosage with 2 added IFX, leading to symptom remission and successful steroid tapering, while one patient experienced continuous non-remission despite increasing the steroid and receiving two infusions of IFX. Of the 8 (32%) ICI rechallenge patients, 4 achieved long-lasting benefit without colitis recurrence. The other 4 experienced recurrent colitis after ICI rechallenge and permanently discontinued ICIs. The median duration from ICI rechallenge to colitis recurrence was shorter than the time to colitis onset. One patient developed steroid-refractory colitis and recovered with one infusion of IFX.ConclusionEndoscopy has value in the evaluation and optimal management of ICI-induced colitis in Chinese cancer patients. IFX is necessary for treating colitis, especially in steroid-refractory/resistant patients. ICI rechallenge can achieve benefit, but permanently discontinuing ICIs is needed if colitis recurs. Future large-scale prospective studies are required for more accurate assessments and validation.

A Case of Successful Treatment Against Toxic Megacolon Associated With Immune Checkpoint Inhibitor-Induced Colitis

A Case of Successful Treatment Against Toxic Megacolon Associated With Immune Checkpoint Inhibitor-Induced Colitis

Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on an IL23/IFNγ axis

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.

Impact of Selective Immunosuppressive Therapy on Subsequent Immune-Related Adverse Events After Immune Checkpoint Inhibitor-Induced Colitis Treatment.

Immune checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs) such as colitis. irAEs can be managed by selective immunosuppressive therapy (SIT) agents such as infliximab and vedolizumab. We aimed to elucidate the incidence of subsequent new irAEs after exposure to SIT by describing patients' clinical course. We conducted a retrospective chart review of adult patients at a tertiary cancer center diagnosed with ICI-mediated colitis (IMC) treated with SIT from February 2013 through October 2021. Patients' clinical courses, treatments, and outcomes of new irAEs after SIT were collected and analyzed. The study included 156 patients. Most were male (67.3%), 44.8% had melanoma, and 43.5% received anti-PD1/L1 ICIs. For IMC treatment, 51.9% received infliximab and 37.8% received vedolizumab. Twenty-six patients (16.6%) resumed ICI treatment after their colitis event. Twenty-five patients (16%) developed a new irAE after receiving SIT. The most common new irAE involved skin (44%), and most (60%) were treated with steroids. Higher diarrhea grade and ≥2 doses of SIT were associated with lower incidence of post-SIT irAEs ( P =0.038, P =0.050). However, the type of SIT or individual dosage of infliximab did not affect the occurrence of subsequent irAEs. New irAEs usually occur more than 6 months after SIT completion for initial colitis event. Severe diarrhea grade and higher number of SIT infusions appeared to have protective effect to lower the occurrence of new irAEs. Otherwise, the type of SIT or individual dosage of infliximab did not affect the occurrence of subsequent irAEs.

Fecal Microbiota Transplantation for Immune Checkpoint Inhibitor-Induced Colitis Is Safe and Contributes to Recovery: Two Case Reports.

Immune checkpoint inhibitors (ICIs) have improved the prognosis in multiple cancer types. However, ICIs can induce immune-related adverse events such as immune-mediated enterocolitis (IMC). The gut microbiota may be implicated in IMC development. Therefore, we investigated fecal microbiota transplantation (FMT) as a treatment option for 2 patients with metastatic cancer suffering from refractory IMC. The patients were treated with, respectively, 1 and 3 FMTs after vancomycin pre-treatment. We monitored defecation frequency, fecal calprotectin, and microbiota composition. After FMT, both patients improved in defecation frequency, were discharged from the hospital, and received lower dosage of immunosuppressive therapy. Patient 1 developed an invasive pulmonary aspergillosis deemed to be related to prolonged steroid exposure. Patient 2 suffered from a Campylobacter jejuni infection after the first FMT and was treated with meropenem, resulting in a low-diversity microbiota profile and increased calprotectin levels and defecation frequency. After a second and third FMT, bacterial diversity increased and defecation frequency and calprotectin levels decreased. Pre-FMT, both patients showed low bacterial richness, but varying bacterial diversity. After FMT, diversity and richness were similar to healthy donor levels. In conclusion, FMT resulted in improvement of IMC symptoms and corresponding microbial changes in 2 cancer patients with refractory IMC. While more research is warranted, microbiome-modulation could be a promising new therapeutic option for IMC.

Position statement on the management of the immune checkpoint inhibitor-induced colitis via multidisciplinary modified Delphi consensus

IntroductionThe 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. AimThe 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. MethodologyThe 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). ConclusionsThe 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.

S2127 Recurrent or Concurrent Colitis: Immune Checkpoint Inhibitor-Induced Colitis vs CMV Colitis

S2127 Recurrent or Concurrent Colitis: Immune Checkpoint Inhibitor-Induced Colitis vs CMV Colitis

S957 Identification and Characterization of a Single-Center Cohort of Patients With Refractory or Relapsing Immune Checkpoint Inhibitor-Induced Colitis

S957 Identification and Characterization of a Single-Center Cohort of Patients With Refractory or Relapsing Immune Checkpoint Inhibitor-Induced Colitis

COLAR: open-label clinical study of IL-6 blockade with tocilizumab for the treatment of immune checkpoint inhibitor-induced colitis and arthritis

BackgroundImmune-related adverse events due to immune checkpoint inhibitors (ICIs) are not always effectively treated using glucocorticoids and it may negatively affect the antitumor efficacy of ICIs. Interventional studies of alternatives...

Biologic Therapy for Refractory Immune Checkpoint Inhibitor Colitis.

Immune checkpoint inhibitors (ICI) are treatments for several cancer types. Pathogenesis of ICI-induced colitis is not yet clearly explained as it can be disguised as another form such as inflammatory bowel disease or IBD. Recent studies revealed that ICI-induced colitis is a unique form of colitis wherein the synergy of regulatory T cells with the gut microbiome is involved. Diagnosis of colitis can be done via endoscopic lesions and histopathological methods. A patient with colitis can be compared with someone who has IBD. Initial treatment is a corticosteroid. Cooperation between gastroenterologists and oncologists is required to understand further the complete diagnosis and management of different behaviors of ICI-induced colitis. Although immunotherapy provides breakthroughs in treating cancer, adverse effects cannot be prevented and have to be carefully addressed. This study aimed to discuss different biologic therapeutic perspectives in treating refractory immune checkpoint inhibitor-induced colitis. This review provided guidelines, challenges, and suggested protocols for drug immunosuppression.

P001 Immune checkpoint inhibitor-induced colitis is mediated by polyfunctional lymphocytes and is dependent on the IL23/IFNg axis

Abstract Background Immune checkpoint inhibitors (CPI) have revolutionised cancer treatment, with previously untreatable disease now amenable to 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. CPI-induced colitis is a common a serious complication. Methods To probe the impact of immune checkpoints on intestinal homeostasis mice were challenged with combination anti-CTLA4 and anti-PD-1 immunotherapy, manipulation of the intestinal microbiota and antibody blockade/depletion studies. Colonic immune responses were profiled using RNA-sequencing, including high-resolution single cell analyses, and flow cytometry. Results CPI colitis was dependent on the composition of the intestinal microbiota and was characterized by remodelling of mucosal lymphocytes with induction of polyfunctional lymphocyte responses characterized by expression of interferon-g (IFNg), other pro-inflammatory cytokines/chemokines (Il22, Il17a Ccl3, Ccl4 and Ccl9) and cytotoxicity molecules (Gzmb, Gzma, Prf1, Nkg7). In comparison with mucosal lymphocytes in the steady state, polyfunctional lymphocytes from both CD4+ and CD8+ lineages upregulated costimulatory molecules and checkpoint molecules in CPI-colitis, indicating that these cells are usually very tightly regulated. CPI-colitis was attenuated following depletion of effector lymphocytes or following blockade of the IL23/IFNg axis. Conclusion This study provides new mechanistic insights into CPI-colitis, identifying polyfunctional, cytotoxic lymphocytes as key mediators of disease. Therapeutic targeting of their effector response or regulatory networks, including the IL23/IFNg axis holds the key to preventing and reversing CPI-colitis.

Differential diagnosis and management of immune checkpoint inhibitor-induced colitis: A comprehensive review.

Immune checkpoint inhibitors (ICIs) are a new class of cancer pharmacotherapy consisting of antibodies that block inhibitory immune regulators such as cytotoxic T lymphocyte antigen 4, programmed cell death 1 and programmed death-ligand 1. Checkpoint blockade by ICIs reactivates a tumor-specific T cell response. Immune-related adverse events can occur in various organs including skin, liver, and gastrointestinal tract. Mild to severe colitis is the most common side effect with some experiencing rapid progression to more serious complications including bowel perforation and even death. Prompt diagnosis and management of ICI-induced colitis is crucial for optimal outcome. Unfortunately, its clinical, endoscopic and histopathologic presentations are non-specific and overlap with those of colitis caused by other etiologies, such as infection, medication, graft-versus-host disease and inflammatory bowel disease. Thus, a definitive diagnosis can only be rendered after these other possible etiologies are excluded. Sometimes an extensive clinical, laboratory and radiologic workup is required, making it challenging to arrive at a prompt diagnosis. Most patients experience full resolution of symptoms with corticosteroids and/or infliximab. For ICI-induced colitis that is treatment-refractory, small scale studies offer alternative strategies, such as vedolizumab and fecal microbiota transplantation. In this review, we focus on the clinical features, differential diagnosis, and management of ICI-induced colitis with special attention to emerging treatment options for treatment-refractory ICI-induced colitis.

Characteristics of Immune Checkpoint Inhibitor-Induced Colitis: A Systematic Review.

Immune checkpoint inhibitors (ICIs) including anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies have been increasingly used for various malignancies. These ICIs activate immune functions to treat malignant tumors; however, this causes characteristic complications called immune-related adverse events (irAE). In the gastrointestinal tract, ICIs cause adverse events such as diarrhea and enterocolitis, thus warranting treatment discontinuation. These irAEs require treatment that suppresses immunity; however, no treatment strategies based on approved guidelines have been reported. This review aimed to investigate the current treatment status for refractory cases of ICI-induced colitis in accordance with their diagnosis, therapy, and prognosis. We systematically reviewed studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist. Two investigators searched PubMed and Scopus in January 2019. We extracted data, including the number of ICI-treated patients developing colitis and diarrhea. The number of cases classified as severe per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) definitions and the progress of corticosteroid-treated and anti-TNF-α- antibody-treated cases (e.g., infliximab) were recorded. Details of further treatment were also recorded for cases that did not improve with antiTNF-α- antibody. Among patients receiving anti-CTLA-4 antibody, corticosteroids were administered to 14.6% of patients, and infliximab was administered to 5.7% of patients. Among patients receiving anti-PD-1/PD-L1 antibody, corticosteroids were administered to 2.37% of patients. For refractory cases unsuccessful with infliximab, the continuation of infliximab every 2 weeks, tacrolimus administration, prolonged corticosteroid treatment, colectomy, or vedolizumab administration were reported. Treatment of ICI-induced colitis is important to avoid the need to discontinue cancer treatment. Many therapeutic agents for inflammatory bowel disease are reportedly effective in treating refractory ICI-induced colitis.

Association of chronic use of proton pump inhibitors with an increased risk of immune checkpoint inhibitor-induced colitis in renal cell carcinoma.

e16550 Background: Immune checkpoint inhibitors (ICI) have become standard of care in metastatic renal cell carcinoma (mRCC) but are associated with immune-related adverse events (irAEs) including immune-related colitis (irC). Growing evidence suggests that proton pump inhibitors (PPIs) are associated with an increased risk of inflammatory bowel disease (IBD). Given the pathophysiological overlap between IBD and irC, we sought to evaluate the relationship between PPI use and irC in mRCC patients. Methods: We performed a retrospective study of adult patients who received ICI for mRCC between 2015 and 2018 at two tertiary care centers. Clinical characteristics, oncological outcomes, irC details, and PPI use were collected by manual chart review. The diagnosis of irC was made via biopsy when available, or when unavailable (or inconclusive) by clinical criteria. Univariable and multivariable logistic regression analyses were conducted to assess PPI use and other potential risk factors of irC. Results: A total of 176 patients received immunotherapy for mRCC, of which 16 (9.1%) were diagnosed with irC. There were no significant differences between patients with and without irC in age, gender, medical comorbidities, RCC subtype, treatment history, and overall survival. However, Caucasian race, exposure to ipilimumab, and PPI use were more frequently observed in patients with irC than those without. Patients with irC presented with elevated stool lactoferrin and calprotectin and a wide range of endoscopic and histologic findings. In univariable and multivariable logistic regression analyses, Caucasian race, exposure to ipilimumab and chronic use of PPIs &gt;8 weeks were significantly associated with irC (Table). Conclusions: PPI use may be a modifiable risk factor for irC development in patients with mRCC.[Table: see text]