Immune checkpoint inhibitors (ICIs) constitute a major breakthrough in the field of cancer therapy; their use has resulted in improved outcomes across various tumour types. However, ICIs can cause a diverse range of immune-related adverse events (irAEs) that present a considerable challenge to the efficacy and safety of these treatments. The gut microbiota has been demonstrated to have a crucial role in modulating the tumour immune microenvironment and thus influences the effectiveness of ICIs. Accumulating evidence indicates that alterations in the composition and function of the gut microbiota are also associated with an increased risk of irAEs, particularly ICI-induced colitis. Indeed, these changes in the gut microbiota can contribute to the pathogenesis of irAEs. In this Review, we first summarize the current clinical challenges posed by irAEs. We then focus on reported correlations between alterations in the gut microbiota and irAEs, especially ICI-induced colitis, and postulate mechanisms by which these microbial changes influence the occurrence of irAEs. Finally, we highlight the potential value of gut microbial changes as biomarkers for predicting irAEs and discuss gut microbial interventions that might serve as new strategies for the management of irAEs, including faecal microbiota transplantation, probiotic, prebiotic and/or postbiotic supplements, and dietary modulations.

Immune checkpoint inhibitor-induced colitis (irColitis) is a common and severe adverse reaction to immune checkpoint inhibitors (ICIs), significantly impacting the treatment outcomes and quality of life of cancer patients. Epidemiological studies indicate that the incidence of irColitis is associated with factors such as the type of ICIs, the patient's gender, age, and medical history. Although the exact pathophysiology remains unclear, irColitis is thought to be related to immune system activation and dysregulation, gut microbiota imbalance, and impaired epithelial barrier function. This review summarized the epidemiology, clinical presentation, diagnostic criteria, and pathogenesis of irColitis. Additionally, the standard and novel therapeutic strategies of irColitis, including corticosteroids, biologics, and gut microbiota interventions, more importantly the potential and application of Traditional Chinese Medicine (TCM). Future researches call for deeper mechanistic investigations, the development of biomarkers, and reveal the integration of TCM therapies within individual immunotherapy frameworks.

Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.

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.

Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%-99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%-100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4+IFN-γ+ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.

Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. Furthermore, ART interruption results in reservoir reactivation and rebound viremia. Both IL-21 and anti-α4β7 improve gut barrier functions, and we hypothesized that combining them would synergize as a dual therapy to improve immunological outcomes in SIV-infected rhesus macaques (RMs). We found no significant differences in CD4+ T cell reservoir size by intact proviral DNA assay. SIV rebounded in both dual-treated and control RMs following analytical therapy interruption (ATI), with time to rebound and initial rebound viremia comparable between groups; however, dual-treated RMs showed slightly better control of viral replication at the latest time points after ATI. Additionally, following ATI, dual-treated RMs showed immunological benefits, including T cell preservation and lower PD-1+ central memory T cell (TCM) frequency. Notably, PD-1+ TCMs were associated with reservoir size, which predicted viral loads (VLs) after ATI. Finally, 16S rRNA-Seq revealed better recovery from dysbiosis in treated animals, and the butyrate-producing Firmicute Roseburia predicted PD-1-expressing TCMs and VLs after ATI. PD-1+ TCMs and gut dysbiosis represent mechanisms of HIV persistence and pathogenesis, respectively. Therefore, combining IL-21 and anti-α4β7 may be an effective therapeutic strategy to improve immunological outcomes for people with HIV.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but are frequently associated with immune-related adverse events (irAEs). This article offers a novel synthesis of findings from both preclinical and clinical studies, focusing on the molecular mechanisms driving irAEs across diverse organ systems. It examines key immune cells, such as T cell subsets and myeloid cells, which are instrumental in irAE pathogenesis, alongside an in-depth analysis of cytokine signaling [interleukin (IL)-6, IL-17, IL-4), interferon γ (IFN-γ), IL-1β, tumor necrosis factor α (TNF-α)], integrin-mediated interactions [integrin subunits αITGA)4 and ITGB7], and microbiome-related factors that contribute to irAE pathology. This exploration of modifiable pathways uncovers new opportunities to mitigate irAEs by using available antibodies (Abs) that target key inflammatory molecules across tumor types, while ideally preserving the antitumor efficacy of ICIs.

Immune checkpoint inhibitors commonly cause gastrointestinal immune-related adverse effects. These patients also carry an increased risk of concomitant infections. This 66-year-old man with immune checkpoint inhibitor colitis was discovered to have concurrent Yersinia and Cytomegalovirus colitis. Such infections may mimic or complicate disease course. Hence, clinicians must monitor patient symptoms, have a low threshold for infectious testing and colonoscopy, and consider treatment strategies to mitigate their risk.

Cancer is one of the most difficult diseases facing modern medicine, and increasing amounts of research and clinical treatments are being applied to the treatment of cancer. Immunotherapy, particularly immune checkpoint inhibitor (ICI) therapy, has revolutionized the treatment and overall survival of patients with several different types of cancer. Approximately one-third of patients treated with ICIs may experience immune-related adverse events (irAEs). Immune checkpoint inhibitor-associated colitis (ICIC) is the most common irAE with an incidence of approximately 8-10%, ICIC usually presents as watery or bloody diarrhea, and if the symptoms are severe, ICI treatment must be interrupted or even terminated. This review summarizes the epidemiology, pathogenesis, clinical characteristics, and therapies of ICIC, focusing on the use of biologics, in order to propose treatment options in different situations to control immune checkpoint inhibitor-related colitis as soon as possible.

To find relevant articles for this narrative review paper, a combination of keywords such as immune checkpoint inhibitor-related colitis, corticosteroids, biologics were searched for in PubMed databases.

The pathogenesis of ICIC is complex and primarily involves antitumor effects and indirect damage to colonic tissues, as well as the activation of specific proinflammatory pathways. Corticosteroids (CSs) are the first line of treatment for ICIC, but steroid-refractory or steroid-resistant cases often occur. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics.

Biologics are currently recommended for the treatment of ICIC but are usually used as a supplement after the failure of first-line CS therapy. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Biologics (alone or in combination with CS) should be considered as an early therapy option for high-risk patients rather than just an escalation after a failure to respond to CS.

Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.

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.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, including the two most common liver tumors, hepatocellular carcinoma and cholangiocarcinoma, but their use in the peri-transplantation period is controversial. ICI therapy aims to heighten cytotoxic T lymphocytes response against tumors. However, tumor recurrence is common owing to tumor immune response escape involving ablation of CTL response by interfering with antigen presentation, triggering CLT apoptosis and inducing epigenetic changes that promote ICI therapy resistance. ICI can also affect tissue resident memory T cell population, impact tolerance in the post-transplant period, and induce acute inflammation risking graft survival post-transplant. Their interaction with immunosuppression may be key in reducing tumor burden and may thus, require multimodal therapy to treat these tumors. This review summarizes ICI use in the liver transplantation period, their impact on tolerance and resistance, and new potential therapies for combination or sequential treatments for liver tumors.

Immune checkpoint inhibitors (ICIs) have emerged as an integral component of the management of various cancers and have contributed to significant improvements in overall survival. Most available ICIs target anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), and anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD1/PDL1). Gastrointestinal immune-related adverse events remain a common complication of ICIs. The predominant manifestations include diarrhea and colitis, which often manifest concurrently as immune-mediated diarrhea and colitis (IMDC). Risk factors for developing these side effects include baseline gut microbiota, preexisting autoimmune disorders, such as inflammatory bowel disease, and type of neoplasm. The hallmark symptom of colitis is diarrhea which may be accompanied by mucus or blood in stools. Patients may also experience abdominal pain, fever, vomiting, and nausea. If not treated rapidly, ICI-induced colitis can lead to serious life-threatening complications. Current management is based on corticosteroids as first-line, and immunosuppressants like infliximab or vedolizumab for refractory cases. Microbiota transplantation and specific cytokines and lymphocyte replication inhibitors are being investigated. Optimal patient care requires maintaining a balance between treatment toxicity and efficacy, hence the aim of this review is to enhance readers' comprehension of the gastrointestinal adverse events associated with ICIs, particularly IMDC. In addition to identifying the risk factors, we discuss the incidence, clinical presentation, workup, and management options of IMDC.

Background and Objectives: Immune check inhibitor (ICI) colitis is one of most common and adverse side effects of ICI. However, there was no case report of ulcerative colitis (UC)-mimicking colitis after atezolizumab use in hepatocellular carcinoma (HCC) to our knowledge. Materials and Methods: We would like to introduce the case of a patient with Stage IV HCC who complained of abdominal pain, diarrhea and rectal bleeding after two cycles of atezolizumab/bevacizumab chemotherapy and was then diagnosed with UC-mimicking colitis. Results: Endoscopy revealed typical findings of UC, suggesting diagnosis of UC-mimicking colitis. The patient was treated with systemic steroids and oral mesalamine, which significantly improved his symptoms, which were also supported by endoscopic findings. The patient resumed chemotherapy with atezolizumab and bevacizumab without any interruption to the chemotherapy schedule. Conclusions: Early endoscopic evaluation is pivotal to diagnosing UC-mimicking colitis. If diagnosed, UC-based treatments such as steroids and mesalamine should be strongly considered. Given previous reports of inflammatory bowel disease (IBD) flare-ups after immunotherapy, routine lower endoscopy, performed together with upper endoscopy before atezolizumab/bevacizumab therapy, is promising to patients.

With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug-drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.

Monoclonal antibody (mAb)-based immunotherapy currently is considered to be an optimal therapeutic approach to cancer treatment, either in combination with surgery, radiation, and/or chemotherapy or alone. Various solid tumors and hematological malignancies have been characterized by distinct molecular targets, which could be utilized as innovative anticancer agents. Notably, receptor tyrosine kinases, including HER2, EGFR, VEGFR, and PDGFR, which act as receptors for growth factors, serve as crucial target proteins, expanding their role in the cancer therapeutic market. In contrast to conventional anticancer agents that directly target cancer cells, the advent of immunotherapy introduces novel approaches, such as immune checkpoint blockers (ICBs) and mAbs targeting surface antigens on immune cells in hematological malignancies and lymphomas. While these immunotherapies have mitigated the acquired resistance observed in traditional targeted therapies, they also exhibit diverse toxicities. Herein, this review focuses on describing the well-established toxicities and newly proposed mechanisms of monoclonal antibody toxicity in recent studies. Understanding these molecular mechanisms is indispensable to overcoming the limitations of mAbs-based therapies, facilitating the development of innovative anticancer agents, and uncovering novel indications for cancer treatment in the future.

Immune check-point inhibitors (ICPi) are immunomodulating agents, which have revolutionized the management of advanced metastatic cancers. Being immunomodulating agents, they are predisposed to causing colitis. This descriptive review article emphasized on the management of ICPi-associated colitis in advanced metastatic cancers. We used PubMed, Google Scholar, Scopus, and Embase databases for literature review, and terminologies commonly searched were "management," "immune check-point inhibitors," "colitis," "metastatic," "cancers," "literature," and "review." We reviewed a total of 11 articles done in the last 15 years relevant to ICPi colitis and its management; all the articles showed that diarrhea and colitis are the most common adverse effects observed in patients on ICPi, but prior to establishing the diagnosis of ICPi-causing colitis, possibility of Clostridium difficle or cytomegalovirus infections should be ruled out. Once the diagnosis of ICPi colitis is established, treatment should be started depending upon the severity of colitis. In mild severity, discontinuation of ICPi can resolve the symptoms but, in most of the patients with moderate to high severity of colitis, corticosteroids are considered a cornerstone treatment. Patients unresponsive to steroid treatment should be re-evaluated for infections after which anti-TNF therapy-infliximab or vedolizumab, cyclosporine, mycophenolate mofetil-can be considered.

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.

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.

Immune checkpoint inhibitors (ICIs) are widely used due to their effectiveness in treating various tumors. Immune-related adverse events (irAEs) are defined as adverse effects resulting from ICI treatment. Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects, such as diarrhea and colitis, which may lead to the cessation of ICIs. Although irAE gastritis is rarely reported, it may lead to serious complications such as gastrorrhagia. Furthermore, irAE gastritis is often difficult to identify early due to its diverse symptoms. Although steroid hormones and immunosuppressants are commonly used to reverse irAEs, the best regimen and dosage for irAE gastritis remains uncertain. In addition, the risk of recurrence of irAE gastritis after the reuse of ICIs should be considered. In this editorial, strategies such as early identification, pathological diagnosis, management interventions, and immunotherapy rechallenge are discussed to enable clinicians to better manage irAE gastritis and improve the prognosis of these patients.

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.

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.

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12-1.64, P = 2×10-03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18-1.88, P = 9×10-04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07-4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Colitis occurs in about 4% of individuals treated with rituximab. Optimal management of rituximab-induced colitis, which does not improve with cessation of the drug and supportive care alone, is poorly defined due to limited evidence. Severe refractory disease can lead to colectomy. We present a case of suspected rituximab-induced colitis occurring in a woman in her 70s suffering from rheumatoid arthritis. The patient achieved full clinical, endoscopic and histological remission of colitis with infliximab therapy. The use of biological therapy to treat rituximab-induced colitis can be a potentially organ-saving rescue therapy; however, it must be balanced against the increased risks of immunosuppression in patients already exposed to rituximab. While more evidence is required to fully understand the efficacy and risks of antitumour necrosis factor therapy in this scenario, our case provides an example of the successful use of infliximab for rituximab-induced colitis, which likely helped the patient avoid a colectomy.

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.

A 68-year-old man developed immune-related adverse event (irAE) colitis after the initiation of nivolumab and ipilimumab combination therapy for malignant melanoma. We diagnosed the patient with grade 3 irAE colitis and started prednisolone (1 mg/kg/day). Although the symptom improved once, it worsened along with the tapering of prednisolone. Therefore, we started infliximab (IFX). However, symptoms did not improve after two doses of IFX. We discontinued IFX and initiated vedolizumab (VED). Because VED alone did not improve the symptom, we started granulocyte-monocyte apheresis (GMA). Twelve weeks after the onset, the colitis was in remission. Therefore, in addition to vedolizumab, GMA may be considered in cases refractory to treatment.

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.

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.

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.

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.

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.

Immune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is a key to advancing precision immuno-oncology. Immune checkpoint inhibitor-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Based on clinical presentation, IMC mimics inflammatory bowel disease, however the link is poorly understood. We hypothesized that genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) may predispose to IMC. We developed and validated polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer who received ICIs. Prevalence of all-grade IMC in our cohort was 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRSUC predicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76, P=0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35, P=0.01). PRSCD was not associated with IMC or severe IMC. The association between PRSUC and IMC (all-grade and severe) was consistent in an independent pan-cancer cohort of patients treated with ICIs. Furthermore, PRSUC predicted severe IMC among patients treated with combination ICIs (OR = 2.20 per SD, 95% CI = 1.07-4.53, P=0.03). This is the first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.