Checkpoint Inhibitor-induced Colitis Research Articles

Effect of fecal transplantation on patient reported outcomes after immune checkpoint inhibitor colitis.

2517 Background: The use of fecal microbiota transplantation (FMT) has traditionally been reserved for the treatment of recurrent Clostridioides difficile infections (CDI). As the gut microbiome has been increasingly acknowledged to play a role in a variety of bodily processes, FMT has seen its application extended to other gastrointestinal disorders. Immune-mediated colitis (IMC) is a similar entity to inflammatory bowel disease and arises as a side effect of immune checkpoint inhibitor therapy to stimulate the immune response. Treatment of IMC is mostly limited to immunosuppressants e.g. corticosteroids, infliximab, and vedolizumab. Cases refractory to such medications pose a significant challenge. FMT has been shown to be a successful treatment in refractory IMC in small case series, further large studies are needed to determine its efficacy. Methods: We measured the efficacy of FMT for refractory IMC among 37 patients via chart review and clinical assessment and patients’ reported outcome (PRO) via established MD Anderson Symptom Inventory (MDASI). Among them, 9 patients had concurrent CDI as well at the time of diagnosis. Results: Fifty-nine patients were included in our study. Most patients had a peak diarrhea grade ≥ 3 (94.9%) and colitis grade ≥ 2 (91.5%). Ulcerous (26, 44.1%) and non-ulcerous (21, 35.6%) inflammation were the predominant endoscopic findings. Fifty-seven (96.6%) patients received corticosteroids, and 54 patients (91.5%) received add-on infliximab or vedolizumab. IMC symptom response was 84.7% after FMT with median time to response of 4 days. The transient complication rate is 30.5% at 7 days and 18.6% at 30 days. Response rate among the 50 patients without concurrent CDI was 86.0%. Fifty (84.7%) patients demonstrated clinical remission by the end of the study period, and 11 (18.6%) were able to resume ICI treatment, and among them, 9 patients remained in remission. A total of 10 patients (16.9%) in our cohort developed recurrent colitis after FMT requiring immunosuppression; 3 of these recurrent cases were triggered by ICI resumption. On the PRO analysis, we observed a favorable trend of significant patient-reported symptom reduction on diarrhea (61% to 11%, p<0.01) and abdominal bloating (36% to 7%, p<0.05) during 12 weeks after FMT. There was a 49.4% reduction of moderate to severe symptoms with only 44% of patients reporting such symptoms after 12 weeks (down from 89%, p<0.01). Conclusions: FMT may serve as a potential treatment option in IMC refractory to standard treatment to avoid long-term steroid dependency and immunosuppression. It is effective to maintain IMC remission with a low complication rate. The role of the gut microbiome in cancer and the implications for FMT remain uncertain and need further elucidation. Clinical trial information: NCT03819296 .

Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis.

Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2Hi CD8 T cells. Cytotoxic GNLYHi CD4 T cells, recirculating ITGB2Hi CD8 T cells and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 therapy compared to anti-PD-1 therapy. Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis.

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.

Immune checkpoint inhibitor colitis, a rising issue in targeted cancer therapy era: A literature review.

Research advances in the oncology treatment field have led to the widespread use of immunotherapy. The usage of immune checkpoint inhibitor (ICI) has improved the survival of cancer patients with metastases. This has also led to the rapidly expanding indications for ICI use. However, ICI usage may lead to toxicity, which may be immune-related, in different organ-specific targets. The immune-related adverse events (irAEs) of ICI may lead to increased morbidity, decreased quality of life, and early termination of ICI. The clinical manifestations of irAEs in the gastrointestinal system are variable, ranging from self-limited to life-threatening or fatal events. In this review article, we would like to focus on discussing ICI-induced colitis, which is one of the most common ICI irAEs in the gastrointestinal tract.

Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis

BackgroundColitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear.MethodsUsing colon biopsies and blood from...

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.

P641 Faecal calprotectin determines non-response to corticosteroids in patients with immune checkpoint inhibitor colitis

Abstract Background Immune checkpoint inhibitor (ICI) therapy has improved survival outcomes in patients with advanced malignancy. ICI colitis (ICI-C) is one of the most common adverse events which often leads to cessation of an otherwise effective therapy.1,2 Corticosteroid therapy remains first-line treatment in patients with ICI-C. The aim of this study was to assess predictors of non-response to corticosteroid therapy to help guide early escalation to biologic therapy. Methods Multicentre retrospective analysis of adults hospitalized with ICI-C between July 2018 to March 2023. ICI-C was defined by patients who had current or prior immunotherapy who presented with diarrhoea with negative infective faeces PCR testing and admission diagnosis of ICI-C by their treating Physician. Baseline demographic, clinical, biochemical, and endoscopic data were collected. Grading of clinical severity on presentation and response to immunosuppression was defined by CTCAE diarrhoea grading with response defined as improvement to grade 1 or less. Results 82 patients were analysed. 31 (38%) female, median age was 65.5 years (IQR 59-72)], 27 (33%) failed corticosteroid therapy and required biologic therapy. 34 (42%) had a faecal calprotectin on admission. On univariable analysis faecal calprotectin emerged as the sole predictor of corticosteroid non-response. ROC analysis identified an optimal faecal calprotectin cut-off of 620 mcg/g to identify corticosteroid non-responders [Sensitivity 75% (57.6-92.7), Specificity 77.8% (52.4-93.6), Accuracy 76.5%, PLR 3.37 (1.36-8.38), NLR 0.32 (0.13-0.78), AUROC 0.76 (0.616-0.911), OR 10.5 (2.24-49.3), PPV 75 (47.6-92.7), NPV 77.8 ( 52.4-93.6)].12/16 (75%) of patients with a faecal calprotectin ≥ 620 required biologic therapy. Conclusion Faecal calprotectin is a predictor of non-response to corticosteroid therapy in patients with immune checkpoint inhibitor colitis. This study identified a faecal calprotectin threshold of 620mcg/g as the optimal cut-off to identify corticosteroid non-response and need for second-line immunosuppression. These findings may help to reduce the need for endoscopic assessment and guide early escalation to biologic therapy. REFERENCES: 1. Fujii T, Colen RR, Bilen MA, et al. Incidence of immune-related adverse events and its association with treatment outcomes: The MD Anderson Cancer Center experience. Invest New Drugs. 2018;36(4):638-646. doi:10.1007/s10637-017-0534-0 2. Wang Y, Abu-Sbeih H, Mao E, et al. Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. Inflamm Bowel Dis. 2018;24(8):1695-1705. doi:10.1093/ibd/izy104.

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

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

Role of proton pump inhibitors in immune checkpoint inhibitor colitis.

743 Background: Proton pump inhibitors (PPIs) are known to be beneficial in symptomatic control of gastroesophageal reflux disease and gastritis which can be a common complication of various cancers specifically gastrointestinal (GI) cancers. Microscopic colitis development has been studied to be associated with PPI use. Immune checkpoint Inhibitor (ICI) colitis is a known adverse effect of Inhibitors of Programmed cell death 1 (PD-1) and its ligand (PD-L1). Previous studies have also shown use of PPIs and NSAIDs are common risk factors which can exacerbate ICI Colitis caused by Inhibitors of PD-1 and PD-L1. This study is designed to observe association of certain drugs especially PPIs in ICI colitis. Methods: This is a single center, retrospective, and observational study that investigated patients treated with PD-1 and PD-L1 Inhibitors for management of any type of cancer between January 2022- September 2023. A list of patients treated with PD-1 and PD-L1 inhibitors was obtained from Inpatient pharmacy records followed by retrospective chart review to look for symptoms of colitis and other medications used by each patient. Primary outcome was to observe the role of PPIs in ICI colitis. Secondary outcomes were to observe the number of patients with GI cancers on PPIs who developed colitis. We also observed the effect of NSAIDs use as a potential risk factor in the population with ICI colitis. Results: The data consisted of 93 patients of which 17 (18.3%) developed colitis. Among this population 13 (76.5%) was ICI colitis, 2 (11.7%) was diverticular colitis and 2 (11.7%) was Infectious colitis. PPI use was seen in 3 out of 13 patients (23%) with ICI colitis. Patients with any type of GI cancer who developed colitis was 5 (25%) and PPI use in ICI colitis was seen in 2 out of these 5 patients. NSAIDs use was seen in 3 (23%) patients with ICI colitis. Conclusions: We did not observe significant association between PPI use and ICI colitis. ICI use becoming increasingly common in oncologic population, larger studies may be needed to further evaluate risk factors associated with ICI colitis in this population.

Histopathologic Features of Unmasked Inflammatory Bowel Disease Following Immune Checkpoint Inhibitor Therapy in Colon Biopsies

Typical immune checkpoint inhibitor-induced colitis (T-ICI) has significant histomorphologic overlap with inflammatory bowel disease (IBD), a distinction further complicated in ICI-treated patients with pre-existing inflammatory bowel disease (P-IBD) and those with potentially "unmasked" inflammatory bowel disease (U-IBD) after ICI therapy. This study describes histopathologic findings seen in U-IBD colonic biopsies and assesses for distinguishing features from T-ICI and P-IBD biopsies. Initial colon biopsies after symptom onset from 34 patients on ICI therapy were reviewed, and histopathologic features were tabulated. U-IBD patients were identified clinically based on rapid toxicity development post-ICI treatment with multiple recurrences after immune suppression, frequently with regional colitis (versus pancolitis). The study cohort was classified into T-ICI (n= 20), P-IBD (n= 9), and U-IBD (n= 5) groups. The predominant histological patterns were diffuse active colitis (35%) in the T-ICI, and chronic active colitis in both the P-IBD (67%) and U-IBD (60%) groups (overall P= .003, P > .05 between the two IBD groups). None of the T-ICI biopsies demonstrated chronicity features (ie, architectural distortion score 2, basal lymphoplasmacytosis, or Paneth cell metaplasia). Only U-IBD biopsies demonstrated basal lymphoplasmacytosis (60% vs 0% in T-ICI/P-IBD, P= .002). Among available follow-up biopsies, chronicity features were present in all (4/4) U-IBD patients, including those without chronicity seen in the initial biopsy, but none (0/7) of T-ICI patients. These early results show that no definite features of chronicity were seen in colon biopsies from T-ICI patients, suggesting that the presence of those features may be a clue to U-IBD in patients without a known IBD diagnosis. Frequent basal lymphoplasmacytosis seen in U-IBD may support a recent onset of mucosal injury and early architectural remodeling.

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.

Focus on Immune Checkpoint Inhibitors-related Intestinal Inflammation: From Pathogenesis to Therapeutical Approach.

Recently, antitumor immunotherapies have witnessed a breakthrough with the emergence of immune checkpoint inhibitors (ICIs) including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. Unfortunately, the use of ICIs has also led to the advent of a novel class of adverse events that differ from those of classic chemotherapeutics and are more reminiscent of autoimmune diseases, the immune-related adverse events (IRAEs). Herein, we performed an insight of the main IRAEs associated with ICIs, focusing on gastroenterological IRAEs and specifically on checkpoint inhibitor colitis, which represents the most widely reported IRAE to date. We comprehensively dissected the current evidence regarding pathogenesis, diagnosis, and management of ICIs-induced colitis, touching upon also on innovative therapies.

S2449 Recurrent Checkpoint Inhibitor Colitis Complicated by Treatment Induced Liver Injury Requiring Vedolizumab Therapy

S2449 Recurrent Checkpoint Inhibitor Colitis Complicated by Treatment Induced Liver Injury Requiring Vedolizumab Therapy

S228 Fecal Transplantation Improved Patients' Reported Outcome After Immune Checkpoint Inhibitor Colitis

S228 Fecal Transplantation Improved Patients' Reported Outcome After Immune Checkpoint Inhibitor Colitis

S314 Efficacy of Infliximab and Vedolizumab in Immune Checkpoint Inhibitor Colitis: A Meta-Analysis

S314 Efficacy of Infliximab and Vedolizumab in Immune Checkpoint Inhibitor Colitis: A Meta-Analysis