Immune checkpoints are crucial in regulating the activation of cell-mediated and humoral immune responses. However, cancer cells hijack this mechanism to evade the immune surveillance and anti-cancer response. Typically, receptors like PD-1 and CTLA4, expressed on immune cells, prevent the activation and differentiation of T cells. They also inhibit the development of autoimmune reactions. However, ligands such as PD-L1 for the receptor PD-1 are also expressed on the surface of cancer cells that help prevent the activation of anti-cancer immune responses by blocking the signalling pathways mediated by PD-1 and CTLA4. Immune checkpoint inhibitors (ICIs) have promising therapeutic efficacy for treating several cancers by activating T cells and their differentiation into effector cells against tumours. Nonetheless, hyperactivated immune cells usually contribute to detrimental issues, also known as immune-related adverse effects (IrAE). IrAEs have been observed in multiple organs, leading to neurological issues, colitis, endocrine dysfunction, renal issues, hepatitis, pneumonitis, and dermatitis. The interplay between hyperactivated T cells and Treg cells helps in orchestrating the development of autoimmunity. Moreover, the crosstalk between proinflammatory interleukins and the development of autoantibodies also mediates the multiorgan effects of ICIs in cancer patients. IrAEs are generally managed by terminating the ICI therapy, reducing the ICI dose, and by using corticosteroids to subvert inflammation. Therefore, the present review aims to delineate the impacts of ICIs on the development of autoimmune diseases and inflammatory outcomes in cancer patients. In addition, mechanistic insight involving immune cells, cytokines, and autoantibodies for ICI-mediated IrAEs will also be discussed with updated findings in this field.

Inflammatory bowel disease (IBD) is an inflammatory disorder in which intestinal homeostasis is disrupted for some reason. Among them, ulcerative colitis (UC) and Crohn's disease (CD) are frequently referred to as IBD in the narrow sense, characterized by relapse episodes and remission periods. The differential diagnosis of IBD involves a broad spectrum of inflammatory or infectious diseases that mimic UC and/or CD, as well as others that may complicate existing IBD. Accordingly, these differential diseases and modifying factors should be considered in their pathological diagnosis, and a careful diagnosis should be made in close collaboration with clinicians. Here, we provide a pathological overview of UC, CD, and their differential diseases, as well as IBD-associated cancers, demonstrating their typical gross and histological features. Further, we introduce a pathological scoring system for biopsy specimens to diagnose IBD that may potentially be integrated into clinical practice.

Immune checkpoint inhibitors (ICIs) have greatly improved cancer treatment by boosting the immune system's ability to target tumors. However, they can also cause serious side effects, particularly in the digestive system. These include immune-related diarrhea, inflammation of the intestines and, less commonly, inflammation of the stomach or esophagus. This review underscores the importance of early detection, accurate diagnosis, and timely treatment to improve patient outcomes. It also highlights the need for further research to develop strategies to reduce gastrointestinal toxicities and enhance the overall effectiveness of ICIs in cancer therapy.

Objectives: Immune-mediated colitis (IMC) is a common immune-related adverse event during immune checkpoint inhibitor (ICI) therapy. This case series and review aimed to highlight atypical cases of IMC and explore the potential of PET/CT to predict imminent ICI colitis. Methods: Through a descriptive, retrospective study at a tertiary cancer center, we identified adult patients receiving ICIs for any cancer between 2010 and 2022 who also underwent PET/CT for routine cancer surveillance during this time. We included patients who had signs and symptoms of colitis and reviewed their surveillance PET/CT scans obtained 2 to 6 weeks before and up to 3 months after diagnosis. Results: For the 33 included patients, surveillance scans were reviewed in collaboration with a nuclear radiologist. A total of 17 patients (51.5%) received combination therapy, while 14 (42.4%) received anti-PD-1/PD-L1 monotherapy. While ICI therapy has a median duration of 6.5 months, most patients (72.7%) had negative surveillance PET/CT for colitis. Diarrhea and colitis severity were similar among those with positive and negative findings for colitis on surveillance PET/CT. The outcomes of colitis were similar, with an 81.8% resolution in patients with negative PET/CT and 71.4% in patients with positive PET/CT. Conclusions: PET/CT imaging did not appear to assist in predicting IMC. This may be due to the long interval between clinical IMC and surveillance PET/CT imaging. The continued use of clinical criteria combined with laboratory markers, e.g., lactoferrin and calprotectin, and endoscopy/histology will enable more accurate detection and timely treatment of IMC.

Immune Checkpoint Inhibitors (ICIs) are monoclonal antibodies that block inhibitory immune targets, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L). Pembrolizumab targets the PD-1 receptor of lymphocytes in lung cancer treatment. ICI checkpoint blockade enhances immunity against cancer cells. However, loss of immunoregulatory control can cause autoimmune reactions in various organs, leading to immune-related adverse events (irAEs). The most common irAE is ICIs-induced colitis, which usually develops 6-8 weeks after ICI initiation and can involve any part of the gastrointestinal system. Herein, we report a presentation of pembrolizumab-induced colitis in a female patient with metastatic lung cancer and review the most recent findings in the model of checkpoint-induced colitis. It was interesting to learn that the colon mucosa may show normal macroscopic findings, but microscopically, immunotherapy-induced autoimmune colitis could be present. Additionally, patients with grade 2 or higher symptoms should have a colonoscopy, receive systemic corticosteroids as treatment, and, based on their response, receive biologic therapy. Here, we present a case report of in a 45-year-old female who has been a smoker for 25 years, without comorbidities, and with metastatic lung cancer who developed colitis after the seventh cycle of pembrolizumab. This case presentation highlights the importance of early recognition and appropriate intervention in order to prevent permanent interruption of treatment with checkpoint inhibitors, as well as prevention of colitis complications.

Immune checkpoint inhibitor (ICI)-induced colitis is a significant adverse event associated with ICI therapy, known to be linked to increased cytotoxic T-cell activity.

To compare T-cell subsets based on the endoscopic features of ICI-induced colitis and to compare these findings with those of inflammatory bowel disease (IBD).

Prospective cohort study.

We analyzed patients with ICI-induced colitis, confirmed through both endoscopic and histological evaluation. Biopsy specimens were examined using multiplex immunohistochemistry to assess their immune cell profile. Clinical outcomes were analyzed. Immune cell profiles were compared based on their endoscopic features and contrasted with those of patients with IBD.

Seventeen patients with ICI-induced colitis were included in the study. All patients showed clinical improvement after treatment, and steroids were administered to 11 patients (64.7%). Based on endoscopic features, the patients were classified as Crohn's disease (CD)-like (n = 3, 17.6%), ulcerative colitis (UC)-like (n = 9, 52.9%), or microscopic colitis (MC)-like (n = 5, 29.4%). In ICI-induced colitis, cytotoxic T cells (Tc cells) were more predominant than helper T cells (Th cells) (p = 0.053), and this trend was most pronounced in the MC-like subtype (p = 0.020). When comparing the number of CD8+ cells infiltrating the crypts, both the UC-like and MC-like subtypes had significantly more infiltrating cells than the CD-like subtype (p = 0.008 and p = 0.016, respectively). In comparison to IBD, IBD exhibited a Th-dominant profile, whereas CD-like ICI-induced colitis had a lower Th cell density than CD (p = 0.032) and UC-like ICI-induced colitis had a higher Tc density than UC (p = 0.045).

Analysis of T-cell subsets of ICI-induced colitis revealed a Tc-dominant profile, contrasting with the Th dominance observed in patients with IBD. The Tc-dominant profile was evident in UC-like and MC-like subtypes, with significant crypt infiltration by CD8+ cells. Tc may play an important role in the pathophysiology of ICI-induced colitis.

The use of immune checkpoint inhibitors (ICIs) for the treatment of various malignancies is increasing. Immune-related adverse events can occur after ICI administration, with gastrointestinal adverse events constituting a significant proportion of these events. When ICI-related diarrhea/colitis is suspected, endoscopic evaluation is recommended to differentiate it from other etiologies and assess the severity of colitis. The distribution of intestinal inflammation in ICI-related colitis demonstrates a high frequency of extensive colitis (23-86%). However, isolated right-sided colitis (3-8%) and ileitis (2-16%) are less prevalent. Endoscopic findings vary and predominantly encompass features indicative of inflammatory bowel disease, including aphthae, ulcers, diffuse or patchy erythema, mucosal edema, loss of vascular pattern, and friability. The presence of ulcers and extensive intestinal inflammation are associated with a reduced response to treatment. Microscopic inflammation can be observed even in endoscopically normal mucosa, underscoring the need for biopsies of seemingly normal mucosa. Histological findings present with acute/chronic inflammation and occasionally exhibit characteristics observed in inflammatory bowel disease, microscopic colitis, or ischemic colitis. The first-line therapeutic choice for ICI-related diarrhea/colitis with a common terminology criteria for adverse events grade of 2 or above is corticosteroids, whereas infliximab and vedolizumab are recommended for refractory cases.

The influence of the gut microbiota on long-term immune checkpoint inhibitor (ICI) efficacy and immune-related adverse events (irAEs) is poorly understood, as are the underlying mechanisms.

We performed gut metagenome and metabolome sequencing of gut microbiotas from patients with lung cancer initially treated with anti-PD-1/PD-L1 therapy and explored the underlying mechanisms mediating long-term (median follow-up 1167 days) ICI responses and immune-related adverse events (irAEs). Results were validated in external, publicly-available datasets (Routy, Lee, and McCulloch cohorts).

The ICI benefit group was enriched for propionate (P = 0.01) and butyrate/isobutyrate (P = 0.12) compared with the resistance group, which was validated in the McCulloch cohort (propionate P < 0.001, butyrate/isobutyrate P = 0.002). The acetyl-CoA pathway (P = 0.02) in beneficial species mainly mediated butyrate production. Microbiota sequences from irAE patients aligned with antigenic epitopes found in autoimmune diseases. Microbiotas of responsive patients contained more lung cancer-related antigens (P = 0.07), which was validated in the Routy cohort (P = 0.02). Escherichia coli and SGB15342 of Faecalibacterium prausnitzii showed strain-level variations corresponding to clinical phenotypes. Metabolome validation reviewed more abundant acetic acid (P = 0.03), propionic acid (P = 0.09), and butyric acid (P = 0.02) in the benefit group than the resistance group, and patients with higher acetic, propionic, and butyric acid levels had a longer progression-free survival and lower risk of tumor progression after adjusting for histopathological subtype and stage (P < 0.05).

Long-term ICI survivors have coevolved a compact microbial community with high butyrate production, and molecular mimicry of autoimmune and tumor antigens by microbiota contribute to outcomes. These results not only characterize the gut microbiotas of patients who benefit long term from ICIs but pave the way for "smart" fecal microbiota transplantation. Registered in the Chinese Clinical Trial Registry (ChiCTR2000032088).

This work was supported by Beijing Natural Science Foundation (7232110), National High Level Hospital Clinical Research Funding (2022-PUMCH-A-072, 2023-PUMCH-C-054), CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&T-B-010).

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.

Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory immune checkpoint molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success and have become the standard of care for many cancers, they are often accompanied by off-target inflammation that can occur in any organ system. These immune related adverse events (irAEs) often require steroid use and/or cessation of ICI therapy, which can both lead to cancer progression. Although irAEs are common, the detailed molecular and immune mechanisms underlying their development are still elusive. To further our understanding of irAEs and develop effective treatment options, there is pressing need for preclinical models recapitulating the clinical settings. In this review, we describe current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis along with their management.

No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms.

This retrospective, international, 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned 1 point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCESs, and clinical symptoms were graded according to a standardized instrument.

A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4. The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo endoscopic subscore of 3 was 74.6%, and the specificity of clinical symptom grading was much lower at 27.4% and 12.3%, respectively. Early endoscopy was associated with timely SIT use (P < .001; r = 0.4084).

This is the largest multicenter study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff of 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

Programmed cell death 1 (PD-1) inhibitors are immune checkpoint inhibitors (ICI) that have demonstrated significant efficacy in treating various advanced malignant tumors. While most patients tolerate treatment well, several adverse drug reactions, such as fatigue, myelosuppression, and ICI-associated colitis, have been reported.

This case involved a 57-year-old male patient with ulcerative colitis complicated by hepatocarcinoma who underwent treatment with tirelizumab (a PD-1 inhibitor) for six months. The treatment led to repeated life-threatening lower gastrointestinal hemorrhage. The patient received infliximab, vedolizumab, and other salvage procedures but ultimately required subtotal colectomy due to uncontrollable massive lower gastrointestinal bleeding. Currently, postoperative gastrointestinal bleeding has stopped, the patient's stool has turned yellow, and his full blood cell count has returned to normal.

This case highlights the necessity of early identification, timely and adequate treatment of ICI-related colitis, and rapid escalation to achieve the goal of improving prognosis.

Proteasome inhibitors (PIs), which cause cell death via tumor suppressor and pro-apoptotic proteins, are integral to treatment of many hematologic malignancies but are limited by their gastrointestinal adverse effects. Evidence regarding these PI-related adverse effects is scant. In this study, we evaluated gastrointestinal adverse events caused by PIs and compared gastrointestinal toxicities between bortezomib, carfilzomib, and ixazomib.

We conducted a retrospective study of cancer patients treated with PIs at a tertiary care cancer center to investigate the clinical characteristics of PI-related gastrointestinal adverse events.

Our sample comprised 973 patients with PI exposure and stool studies ordered between January 2017 and December 2022. Of these, 193 patients (20%) had PI-related gastrointestinal toxicity based on clinical symptoms and stool study results. The most common symptom was diarrhea, present in 169 (88% of those with gastrointestinal toxicity). Twenty-two (11%) required hospitalization, and 71 (37%) developed recurrence of symptoms. Compared to bortezomib or carfilzomib, ixazomib had a longer interval from PI initiation to the onset of gastrointestinal symptoms (313 days vs 58 days vs 89 days, p = 0.002) and a significantly lower percentage of diarrhea-predominant presentation of gastrointestinal toxicity (71% vs 96% vs 91%, p = 0.048).

While PI-related gastrointestinal toxicities have various presentations and courses based on different regimens, the vast majority of patients presented with milder disease behavior. Despite a considerably high rate of hospitalization and recurrence after treatment necessitating optimization of clinical management, our cohort demonstrates favorable outcomes without long-term consequences.

Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis.

This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed.

Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis.

Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

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 inhibitors (ICIs) are effective oncologic agents which frequently cause immune-related adverse events (irAEs) which can impact multiple organ systems. Onco-Gastroenterology is a novel and emerging subspecialty within gastroenterology focused on cancer treatment-related complications. Gastroenterologists must be prepared to identify and manage diverse immune-mediated toxicities including enterocolitis, hepatitis, pancreatitis and other ICI-induced toxicities.

To provide a narrative review of the epidemiology, diagnostic evaluation and management of checkpoint inhibitor-induced gastrointestinal and hepatic toxicities.

We searched Cochrane and PubMed databases for articles published through August 2023.

Gastrointestinal and hepatic irAEs include most commonly enterocolitis and hepatitis, but also pancreatitis, oesophagitis, gastritis, motility disorders (gastroparesis) and other rarer toxicities. Guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology and European Society for Medical Oncology, in combination with emerging cohort and clinical trial data, offer strategies for management of ICI toxicities. Evaluation of irAEs severity by formal classification and clinical stability, and a thorough workup for alternative etiologies which may clinically mimic irAEs underlie initial management. Treatments include corticosteroids, biologics and other immunosuppressive agents plus supportive care; decisions on dosing, timing and choice of steroid adjuncts and potential for subsequent checkpoint inhibitor dosing are nuanced and toxicity-specific.

Expanding clinical trial and cohort data have clarified the epidemiology and clinical characteristics of gastrointestinal, pancreatic and hepatic toxicities of ICIs. Guidelines, though valuable, remain based principally on retrospective cohort data. Quality prospective, controlled studies may refine algorithms for treatment and potential immunotherapy rechallenge.

Colitis is a common manifestation of immune checkpoint inhibitor (ICI) toxicity and can present with varied histologic patterns of inflammation, some of which have been shown to be associated with specific ICI drug types. Although the histologic features of ICI colitis seen at the time of diagnosis have been described, there have been few reports following these patients over time. We evaluated initial and follow-up biopsies in 30 patients with ICI colitis and found that 37% of patients developed a different pattern of injury on follow-up biopsy compared to the initial biopsy. Patients with a different inflammatory pattern were more likely to have restarted ICI therapy before their follow-up biopsy (64%) compared to those without a change in inflammatory pattern (11%; P < 0.01). The majority of these patients had changed ICI drug types (86%). Additionally, many cases changed to an inflammatory bowel disease (IBD)-like pattern (36%), raising a question of de novo IBD. However, all of our patients with an IBD-like pattern experienced sustained resolution of symptoms without steroids or other immunosuppressive medications following discontinuation of ICI therapy, consistent with a diagnosis of ICI toxicity. Our findings suggest that follow-up biopsies in patients with ICI colitis may show a different histology and that this does not necessarily warrant a change in the histologic diagnosis to another disease.

No 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.

Serum 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.

Anti-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.

Anti-integrin αvβ6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.

Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) poses a major clinical challenge to ICI therapy for cancer, with 13% of cases halting ICI therapy and ICI-IA being difficult to identify for timely referral to a rheumatologist. The objective of this study was to rapidly identify ICI-IA patients in clinical data and assess associated immune-related adverse events (irAEs) and risk factors.

We conducted a retrospective study of the electronic health records (EHRs) of 89 patients who developed ICI-IA out of 2451 cancer patients who received ICI therapy at Northwestern University between March 2011 to January 2021. Logistic regression and random forest machine learning models were trained on all EHR diagnoses, labs, medications, and procedures to identify ICI-IA patients and EHR codes indicating ICI-IA. Multivariate logistic regression was then used to test associations between ICI-IA and cancer type, ICI regimen, and comorbid irAEs.

Logistic regression and random forest models identified ICI-IA patients with accuracies of 0.79 and 0.80, respectively. Key EHR features from the random forest model included ICI-IA relevant features (joint pain, steroid prescription, rheumatoid factor tests) and features suggesting comorbid irAEs (thyroid function tests, pruritus, triamcinolone prescription). Compared to 871 adjudicated ICI patients who did not develop arthritis, ICI-IA patients had higher odds of developing cutaneous (odds ratio [OR]=2.66; 95% Confidence Interval [CI] 1.63-4.35), endocrine (OR=2.09; 95% CI 1.15-3.80), or gastrointestinal (OR=2.88; 95% CI 1.76-4.72) irAEs adjusting for demographics, cancer type, and ICI regimen. Melanoma (OR=1.99; 95% CI 1.08-3.65) and renal cell carcinoma (OR=2.03; 95% CI 1.06-3.84) patients were more likely to develop ICI-IA compared to lung cancer patients. Patients on nivolumab+ipilimumab were more likely to develop ICI-IA compared to patients on pembrolizumab (OR=1.86; 95% CI 1.01-3.43).

Our machine learning models rapidly identified patients with ICI-IA in EHR data and elucidated clinical features indicative of comorbid irAEs. Patients with ICI-IA were significantly more likely to also develop cutaneous, endocrine, and gastrointestinal irAEs during their clinical course compared to ICI therapy patients without ICI-IA.

Immune checkpoint inhibitors have transformed the treatment paradigm for various types of cancer. Nonetheless, with the utilization of these groundbreaking treatments, immune-related adverse events (irAEs) are increasingly encountered. Colonic and hepatic involvement are among the most frequently encountered irAEs. Drug-induced side effects, infectious causes, and tumor-related symptoms are the key differentials for irAE complications. Potential risk factors for the development of irAEs include combination use of immune checkpoint inhibitors, past development of irAEs with other immunotherapy treatments, certain concomitant drugs, and a pre-existing personal or family history of autoimmune illness such as inflammatory bowel disease. The importance of early recognition, timely and proper management cannot be understated, as there are profound clinical implications on the overall cancer treatment plan and prognosis once these adverse events occur. Herein, we cover the clinical management of the well-established gastrointestinal irAEs of enterocolitis and hepatitis, and also provide an overview of several other emerging entities.

Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.

The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.

Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Immune checkpoint inhibitors can stimulate antitumor immunity but can also induce toxicities termed immune-related adverse events (irAEs). Colitis is a common and severe irAE that can lead to treatment discontinuation. Mechanistic understanding of gut irAEs has been hampered because robust colitis is not observed in laboratory mice treated with checkpoint inhibitors. We report here that this limitation can be overcome by using mice harboring the microbiota of wild-caught mice, which develop overt colitis following treatment with anti-CTLA-4 antibodies. Intestinal inflammation is driven by unrestrained activation of IFNγ-producing CD4+ T cells and depletion of peripherally induced regulatory T cells through Fcγ receptor signaling. Accordingly, anti-CTLA-4 nanobodies that lack an Fc domain can promote antitumor responses without triggering colitis. This work suggests a strategy for mitigating gut irAEs while preserving antitumor stimulating effects of CTLA-4 blockade.

New oncologic treatments, particularly immunotherapy (IT), have revolutionized the treatment of advanced-stage malignant tumors. Immune checkpoint inhibitors are the main form of IT and act by increasing T cell activity and the organism's immune response against neoplastic cells. Targeted therapy is another form of IT that acts by inhibiting oncogenes or inflammation signaling and tumor angiogenesis pathways. However, these mechanisms of tumor destruction can interfere with the host's immune self-tolerance or with the mechanisms of epithelial tissue repair and predispose to immune system-mediated adverse events that can affect multiple organs, including the digestive tract. The gastrointestinal manifestations of damage caused by IT can range from low-grade mucositis to ulceration, and in some cases, necrosis and perforation. Any part of the gastrointestinal tract can be affected, but there is greater involvement of the small bowel and colon, with a pattern similar to that seen in inflammatory bowel disease. The most common clinical manifestation is chronic diarrhea. The differential diagnosis includes enteropathogenic infections, especially those caused by opportunistic microorganisms; adverse drug reactions; and other inflammatory and malabsorption disorders. Treatment is guided by damage severity. Mild cases can be treated with antidiarrheals and rehydration in the outpatient setting; moderate cases with hospitalization, systemic steroids, and temporary suspension of IT; and severe cases with immunosuppressants or biologic agents and definitive suspension of IT.

Microscopic colitis is an inflammatory disease of the colon that presents as watery diarrhea with minimal to normal endoscopic changes on colonoscopy. It encompasses two common subtypes, lymphocytic colitis and collagenous colitis, which are both treated similarly.Immune checkpoint inhibitor colitis is among the most common immune-related adverse events. Endoscopic and histological findings range from normal colonic mucosa to inflammatory bowel like changes. This review article provides update in treatment and management of microscopic colitis and immune checkpoint inhibitor colitis (ICPi colitis).

Recent studies on microscopic colitis have focused on the successful use of immunomodulators such as biologics for treatment of budesonide refractory microscopic colitis cases. Microscopic colitis does not confer an added risk for colorectal cancer.With the increasing usage of immunotherapy agents, immune checkpoint inhibitor colitis is becoming more common. ICPi colitis can be successfully managed with steroids, with treatment stepped up to biologics for moderate to severe cases or for mild cases that do not respond to steroids. Immunotherapy agents can be carefully re-introduced in mild cases, after treatment of ICPi colitis.

Biologics can be used to treat budesonide refractory microscopic colitis. ICPi colitis can be managed with steroids and biologics in moderate to severe cases.

Immune checkpoint inhibitors have revolutionized the management of many advanced cancers by producing robust remissions. They mostly target two immune regulatory pathways: cytotoxic T lymphocyte antigen-4 and programmed death-1 or its ligand. However, a flip side is the immune-related adverse events (irAEs) commonly affecting the gastrointestinal (GI) tract that can cause treatment interruptions or discontinuation. This practical review discusses the clinical and histopathologic findings of irAEs encountered in the luminal GI tract, along with histopathologic differentials that can mimic varied inflammatory, infectious, or other medication-associated etiologies and the importance of clinico-pathologic correlation for an accurate diagnosis.

Immune checkpoint inhibitors (ICIs) have improved the outcomes of cancer patients. However, ICIs often lead to colitis/diarrhea. This study aimed to assess the treatment of ICIs-associated colitis/diarrhea and outcomes.

PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies which investigated the treatment and outcomes of colitis/diarrhea developing in patients who received ICIs. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea as well as the pooled rates of response to treatment, mortality, and ICIs permanent discontinuation and restarts in patients with ICIs-associated colitis/diarrhea were estimated using a random-effects model.

Among the 11,492 papers initially identified, 27 studies were included. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea were 17%, 3%, 17%, 13%, and 15%, respectively. The pooled rates of overall response, response to corticosteroid therapy, and response to biological agents were 88%, 50%, and 96%, respectively. The pooled short-term mortality in patients with ICIs-associated colitis/diarrhea was 2%. The pooled incidences of ICIs permanent discontinuation and restarts were 43% and 33%, respectively.

ICIs-associated colitis/diarrhea is common, but rarely lethal. Half of them are responsive to corticosteroid therapy. There is a fairly high rate of response to biological agents in steroid-refractory colitis/diarrhea patients.

Toripalimab, a specific immune checkpoint inhibitor targeting the programmed death 1 (PD-1) receptor, represents a novel immunotherapeutic approach for advanced nasopharyngeal carcinoma, showing promising curative potential. However, it is not without drawbacks, as some patients experience immune-related adverse events (irAEs) associated with this treatment, and there remains a limited body of related research. Here, we present a case of advanced nasopharyngeal carcinoma in a patient who developed colitis as an irAE attributed to Toripalimab. Subsequent to Toripalimab treatment, the patient achieved complete remission. Notably, the development of colitis was accompanied by inflammatory manifestations evident in colonoscopy and pathology results. Further investigation revealed cytomegalovirus (CMV) infection, detected through immunohistochemistry in 11 colon biopsies. Subsequent treatment with ganciclovir and steroids resulted in symptom relief, and colonoscopy indicated mucosal healing. Our case highlights the association between irColitis induced by Toripalimab and CMV infection. Toripalimab demonstrates remarkable efficacy in treating advanced nasopharyngeal carcinoma, albeit with a notable risk of irAEs, particularly in the form of colitis. The link between symptoms and endoscopic pathology findings in irColitis is noteworthy. Standardized biopsy procedures can effectively confirm the diagnosis of CMV infection. Our findings may provide valuable guidance for managing acute CMV infection and irAEs associated with Toripalimab in the treatment of nasopharyngeal carcinoma in the future.

Immune checkpoint inhibition therapy (ICIT) is an emerging field in oncology especially opening new horizons to chemotherapy refractory patients. However, immune-related adverse events (irAEs) and undesired response patterns such as progression after the initial good response in a subset of patients pose a major challenge and drawback to ICIT. This paper provides deep insight into ICIT related bottlenecks and corresponding effective management and combat strategies for very complex complications.

The relevant literatures from PubMed have been reviewed. Based on obtained information, rigorous and exhaustive analyses have been made to present novel methods and strategies against ICIT drawbacks and bottlenecks.

The results show that baseline biomarker tests are very crucial to identify suitable candidates for ICIT and frequent assessments throughout ICIT help to recognize possible irAEs at early stages. Equally important are the necessity for mathematical definitions for the ICIT success rate and optimum duration, and the development of combat mechanisms against loss of sensitivity within the tumor microenvironment (TME).

Rigorous management approaches are presented for mostly observed irAEs. Furthermore, for the first time in the literature, a non-linear mathematical model is invented to measure the ICIT success rate and to decide about the optimum ICIT duration. Finally, a strategy against tumor plasticity is introduced.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the field of oncology over the past decade, leading to durable remissions in some patients but also producing a wide spectrum of treatment-limiting inflammatory toxicities that are referred to as immune-related adverse events (irAEs). Although irAEs can involve any organ system in the body, they most commonly affect the barrier tissues, including the gastrointestinal tract with colitis and enterocolitis affecting a significant fraction of patients on ICIs. We are beginning to understand the mechanisms that drive ICI colitis, with early experiments indicating a role for CD8+ resident memory T cells (TRMs) in the gut, which become activated and differentiate into cytotoxic cells in response to ICI therapy. The risk factors that define who will develop ICI colitis are not understood and substantial efforts are underway to identify potential biomarkers for risk of this and other toxicities. Optimal management of ICI colitis is also an area of active investigation. Current standard treatments are based largely on small, retrospective analyses, and while drugs like systemic glucocorticoids or the TNFα inhibitor infliximab do appear to be highly active in ICI colitis, the impact of these therapies on antitumor responses is poorly understood. As discussed in this review, future work will have to define the immune mechanisms driving ICI colitis in more detail and in comparison to antitumor responses in order to identify candidate pathways that can be targeted to improve ICI colitis without interfering in antitumor immunity. Studying these interventions will require randomized, controlled trials with both tumor and colitis endpoints, a goal that will necessitate collaboration across institutions and funding agencies. We are at a point where such collaborative trials are feasible, and have the potential to greatly improve the care of patients with ICI colitis as well as other irAEs.