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Introduction: The development of immune checkpoint inhibitors (ICIs) represents one of the most significant advancements in cancer treatment over the past decade. Nivolumab, a widely used ICI, has been incorporated into the therapeutic regimens for various cancers. As with any drug, this drug also has side effects, including class-specific immune-related adverse effects (irAEs). Although irAEs are not rare, their diagnosis can be challenging. This study examines the emergency department (ED) visits of patients undergoing nivolumab therapy, focusing on diagnostic challenges, evaluating the management, and outcomes of irAEs in the ED setting. Material and methods: A retrospective cohort study was conducted on adult patients who received nivolumab therapy for any cancer between April 1, 2018, and March 31, 2023, at a large, urban tertiary care center. In this study, we evaluated the ED visits of patients receiving nivolumab. In addition to previous studies, we evaluated irAEs in detail (percentage, recognizability, risk factors, reasons for late recognition, and outcome). Patient data were collected from electronic medical records and patient’s medical files. The anamnesis, laboratory, and imaging results, ED management, and consultation notes were examined separately for each ED visit. Logistic regression models were employed to identify significant univariable predictors of ED visits and irAEs. Results: A total of 199 patients were included in the study, all of whom had metastatic cancer. Of these, 154 patients (77.4%) received nivolumab therapy for non-small cell lung cancer. Most patients (71.9%, n = 143) had at least one additional comorbidity. One hundred and eleven patients (55.8%) presented to the ED. Hypertension (OR: 2.425, 95% CI: 1.226–4.795, p = 0.011) and chronic obstructive pulmonary disease (OR: 2.489, 95% CI: 1.133–5.468, p = 0.023) were identified as risk factors for ED visits. A total of 21 irAEs were diagnosed (14 in ED, 6 in the oncology clinic, and 1 in the inpatient ward). Univariate analysis found no significant association between irAE diagnosis and any specific factors. Conclusion: A significant proportion of the patients treated with nivolumab for advanced cancer present to ED for ICI-related adverse events, although most cases were not attributable to irAEs. Due to the vague symptomatology of irAEs, their recognition and diagnosis in the ED can be challenging. Close collaboration between ED physicians and oncologists is paramount to the management of patients with cancer in the ED. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICI) represent a breakthrough in oncology in terms of prognosis and safety. They now constitute a cornerstone in the management of metastatic melanoma. However, a new kind of adverse event called immune‐related adverse events (irAE) has emerged. These irAE could be conceptually considered as an indicator of the antitumoral immune response, but the association between irAE and prognosis is still a matter of debate. Objective: The purpose of this study was to investigate the association between the overall survival (OS) and the prevalence of irAE in melanoma. Methods: MEDLINE/PubMed, WebofScience, ClinicalTrials, and WHOTrials databases were searched to identify phase 3 randomized controlled trials (RCT) assessing ICI in melanoma and published up to April 2021. A weighted regression was performed to estimate this association according to standard method of surrogacy analysis. Results: A total of 14 RCT including 7646 patients (median age: 59.3 years) with melanoma were included. All types of ICI were represented (ipilimumab, tremelimumab, pembrolizumab, nivolumab, atezolizumab, as well as ipilimumab and nivolumab combination). irAE were frequent but rarely fatal. The combination of ICI caused more irAE than anti‐PD1 (or PDL1) and anti‐CTLA4 monotherapies. No relationship was found between the occurrence of irAE and OS (beta coefficient 0.078, R2 3%, p = 0.52), nor between cutaneous irAE and OS (beta coefficient 0.080, R2 6%, p = 0.33). Conclusion: Although limited by the heterogeneity of ICI included in the regression and the low number of included RCT, the present study suggests an absence of association between irAE and prognosis in melanoma. [ABSTRACT FROM AUTHOR]

Cancer‐associated dermatomyositis (CAD), a paraneoplastic syndrome characterized by dermatomyositis (DM), frequently presents in association with small cell lung cancer (SCLC). Although the advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, their efficacy and safety in patients with concurrent autoimmune diseases (AD) and malignancies remains uncertain. Several studies have suggested the safe administration of ICIs in patients with AD, indicating that successful cancer therapy can alleviate CAD symptoms. Conversely, other studies have raised concerns about the potential for ICIs to exacerbate AD flares or immune‐related adverse events (irAEs). A comparative analysis of two cases from our institution emphasizes the variability in ICI responses among SCLC patients with CAD. One patient, previously reported as a case study, exhibited significant clinical improvement in DM symptoms after ICI administration, whereas the other developed severe exfoliative skin changes and experienced an unfavorable prognosis. This variability emphasizes the need for careful patient selection and close monitoring during ICI treatment. We hypothesized that overweight or obese individuals and those with severe initial skin lesions and elevated lactate dehydrogenase levels are more susceptible to developing irAEs following ICI therapy. Therefore, caution is advised when considering immunotherapy in these patients. [ABSTRACT FROM AUTHOR]

Background: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs). Methods: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion. Results: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34–0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40–0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03–0.85). Conclusion: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs. [ABSTRACT FROM AUTHOR]

Summary: Immune checkpoint inhibitor therapies act through blockade of inhibitory molecules involved in the regulation of T cells, thus releasing tumor specific T cells to destroy their tumor targets. However, immune checkpoint inhibitors (ICI) can also lead to a breach in self‐tolerance resulting in immune‐related adverse events (irAEs) that include tissue‐specific autoimmunity. This review addresses the question of whether the mechanisms that drive ICI‐induced irAEs are shared or distinct with those driving spontaneous autoimmunity, focusing on ICI‐induced diabetes, ICI‐induced arthritis, and ICI‐induced thyroiditis due to the wealth of knowledge about the development of autoimmunity in type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. It reviews current knowledge about role of genetics and autoantibodies in the development of ICI‐induced irAEs and presents new studies utilizing single‐cell omics approaches to identify T‐cell signatures associated with ICI‐induced irAEs. Collectively, these studies indicate that there are similarities and differences between ICI‐induced irAEs and autoimmune disease and that studying them in parallel will provide important insight into the mechanisms critical for maintaining immune tolerance. [ABSTRACT FROM AUTHOR]

The introduction of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment standards and significantly enhanced patient prognoses. However, the utilization of these groundbreaking therapies has led to the observation and reporting of various types of adverse events, commonly known as immune-related adverse events (irAEs). In the following article, we present four patients who encountered uncommon toxicities induced by ICIs. The first patient was a 59-year-old female diagnosed with stage 4 lung adenocarcinoma. She received immunotherapy (pembrolizumab) together with chemotherapy and subsequently developed autonomic neuropathy (AN). The next two patients also received chemo-immunotherapy (pembrolizumab) and were both 63-year-old males with stage 4 lung adenocarcinoma. One of the two experienced palmoplantar keratoderma, while the other presented with Reiter's syndrome (urethritis, conjunctivitis and arthritis). The 4th patient, an 80-year-old male with stage 4 squamous cell carcinoma of the lung, received chemo-immunotherapy (pembrolizumab) and developed myasthenia gravis. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) are commonly associated with thyroid immune-related adverse events, yet the mechanism has not been fully elucidated. We aimed to further explore the mechanism of ICI-induced thyroid dysfunction by assessing changes induced in the thyroid transcriptome by ICI treatment (αPD-1/αPD-L1) in a lung cancer murine model. RNA-sequencing of thyroid tissues revealed 952 differentially expressed genes (DEGs) with αPD-1 treatment (|fold-change| ≥1.8, FDR < 0.05). Only 35 DEG were identified with αPD-L1, and we therefore focused on the αPD-1 group alone. Ingenuity Pathway Analysis revealed that of 952 DEGs with αPD-1 treatment, 362 were associated with functions of cell death and survival, with predicated activation of pathways for apoptosis and necrosis (Z = 2.89 and Z = 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z = −6.22 and Z = −6.45, respectively). Compared to previously published datasets of interleukin-1β and interferon γ-treated human thyroid cells, apoptosis pathways were similarly activated. However, unique changes related to organ inflammation and upstream regulation by cytokines were observed. Our data suggest that there are unique changes in gene expression in the thyroid associated with αPD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis. [ABSTRACT FROM AUTHOR]

Background: This study aims to review and summarize the current up to date literature that explore the current treatment approaches to immune mediated colitis and the role of surgical specialties in the landscape of management. Methods: A narrative review of papers was performed following a literature search through Medline, EMBASE and Cochrane Central databases pertaining to immune mediated colitis as an adverse event of cancer immunotherapy. Results: Current guidelines for the diagnosis and treatment of immune mediated colitis mirror the approach to the workup of inflammatory bowel disease and guided by treating oncology and gastroenterology specialties. Immune mediated colitis however relies on surgical specific skills as a consequence of obtaining a diagnosis as well as in the management of complications that may arise. Conclusion: Immune mediate colitis management has largely been under the purview of medical specialties. This review explores the current landscape of managing immune mediated colitis from a surgical perspective and highlights key areas in which surgeons can engage in the multidisciplinary care of this condition. To facilitate prompt diagnosis and management of immune‐mediated colitis, there is an increasing necessity for surgeons to become familiar with the latest multidisciplinary approaches and recommendations. [ABSTRACT FROM AUTHOR]

Background: The use of immune checkpoint inhibitors (ICI) has transformed cancer treatment. Subsequent ICI use has become increasingly common following disease progression. We aim to evaluate the safety and tolerability of the sequential ICI treatment modality. Methods: Retrospective review of confirmed carcinoma from January 2014 to December 2018. Patients were categorized into "initial ICI arm" and "sequential ICI arm" defined as patients receiving single, dual or chemo-immunotherapy ICI following an initial ICI regimen. Primary outcome was the development of a new or recurrent immune related adverse event (irAE) during sequential therapy. Secondary outcomes were the number of cycles prior to the development of irAE and grade of irAE. Results: A total of 483 patients received ICI during the timeframe. Of those, 22 patients received sequential ICI. The diagnoses included ten lung cancer, seven melanoma, four renal cell carcinoma and one bladder cancer. 16 patients received single agent ICI following the initial ICI, three patients received dual ICI following the initial ICI, one patient received chemotherapy-immunotherapy following initial ICI, and two patients received chemo-immunotherapy after dual ICI. Four patients developed new irAE and one patient developed the same irAE on sequential treatment. A higher proportion of patients experienced grade 3 irAE in the sequential arm compared to the initial ICI arm (p = 0.03). No statistical difference was found between the development of irAE and the number of cycles prior to development of irAE in either treatment groups (p = 0.5). Conclusion: Our data shows overall safety of sequencing ICI when close monitoring was employed. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint blockade (ICB) elicits a strong and durable therapeutic response, but its application is limited by disparate responses and its associated immune-related adverse events (irAEs). Previously, in a murine model of lymph node (LN) metastasis, we showed that intranodal administration of chemotherapeutic agents using a lymphatic drug delivery system (LDDS) elicits stronger therapeutic responses in comparison to systemic drug delivery approaches, while minimizing systemic toxicity, due to its improved pharmacokinetic profile at the intended site. Importantly, the LN is a reservoir of immunotherapeutic targets. We therefore hypothesized that metastatic LN-targeted ICB can amplify anti-tumor response and uncouple it from ICB-induced irAEs. Methods: To test our hypothesis, models of LN and distant metastases were established with luciferase expressing LM8 cells in MXH10/Mo-lpr/lpr mice, a recombinant inbred strain of mice capable of recapitulating ICB-induced interstitial pneumonia. This model was used to interrogate ICB-associated therapeutic response and immune related adverse events (irAEs) by in vivo imaging, high-frequency ultrasound imaging and histopathology. qPCR and flowcytometry were utilized to uncover the mediators of anti-tumor immunity. Results: Tumor-bearing LN (tbLN)-directed CTLA4 blockade generated robust anti-tumor response against local and systemic metastases, thereby improving survival. The anti-tumor effects were accompanied by an upregulation of effector CD8T cells in the tumor-microenvironment and periphery. In comparison, non-specific CTLA4 blockade was found to elicit weaker anti-tumor effect and exacerbated ICI-induced irAEs, especially interstitial pneumonia. Together these data highlight the importance of tbLN-targeted checkpoint blockade for efficacious response. Conclusions: Intranodal delivery of immune checkpoint inhibitors to metastatic LN can potentiate therapeutic response while minimizing irAEs stemming from systemic lowering of immune activation threshold. [ABSTRACT FROM AUTHOR]

Immune-related adverse events (irAEs) are side effects of immune checkpoint inhibitor therapy (ICI). While common irAEs have been well characterized, there are more limited data on rare immune related adverse events (RirAEs) due to low incidence. Lack of characterization of these entities has led to difficulties in accurate diagnosis and management. Here, we conducted a multi-institution analysis of all patients with stage III/IV melanoma who developed RirAEs after being treated with ICIs (anti-PD-1/L1, anti-CTLA-4, and combination PD-1/CTLA-4 blockade) at three institutions (Vanderbilt University Medical Center, Massachusetts General Hospital, and Melanoma Institute of Australia). RirAEs were defined as those occurring in approximately <1% of patients treated with anti-PD-1 or <2% with combination. Of 2834 patients who received ICIs, 82 developed RirAEs and were more common with combination PD-1/CTLA-4 blockade (4.6%) vs. anti-PD-1/L1 agents (2.8%). Overall median time from ICI start to RirAE was 86 days (interquartile range 42–235 days) with significantly earlier onset in combination therapy (p < 0.001). The spectrum of RirAEs spanned across several organ systems. Most RirAEs were grade 2 (57 [41.3%]) and grade 3 (40 [29.0%]) with relatively few grade 4 (11 [8.0%]) or 5 (5 [3.6%]) events. Steroid re-escalation (21.4%) or additional immunosuppression (13.8%) were commonly required. RirAE recurrence occurred in 22.6% with ICI rechallenge; 37.1% had new irAEs with rechallenge. In conclusion, RirAEs associated with ICIs in melanoma patients occurred, in aggregate, in 2–5% of patients treated with anti-PD-1-based therapy. Steroid re-escalation and alternative immunosuppression use were frequently required but fatal irAEs were fairly uncommon. [ABSTRACT FROM AUTHOR]

Background: Immune related adverse events impacting the liver are common from immune checkpoint inhibitor (ICI) therapy; however, there is little data regarding the subclinical impact of ICIs on liver inflammation. The study aims to determine whether ICI therapy affects liver attenuation and liver enzymes in melanoma patients with and without hepatic steatosis.Methods: A retrospective, cohort study was conducted of patients with advanced melanoma treated with ICI therapy who received serial PET-CT scans at the Vanderbilt University Medical Center (VUMC). Primary outcomes included: liver attenuation measured by PET-CT/non-contrast CT and liver enzymes. Hepatic steatosis was diagnosed by radiologists on clinical imaging.Results: Among 839 patients with advanced melanoma treated with ICIs, 81 had serial PET-CT scans approximately 12 months apart and long-term survival; of these 11 patients had pre-existing steatosis/steatohepatitis. Overall, ICI was not associated with significant increases in liver enzymes in all patients; modest decreases in liver enzymes were observed in patients with pre-existing steatosis/steatohepatitis. Similarly, liver attenuation did not change from baseline to post-treatment (58.44 vs 60.60 HU, + 2.17, p = 0.055).Conclusions: ICIs may not chronically affect liver enzymes or liver attenuation, a non-invasive measure of liver fat content and inflammation, in the general population or in those with pre-existing steatosis/steatohepatitis. [ABSTRACT FROM AUTHOR]

We herein report a 79‐year‐old woman who underwent surgery had recurred non‐small cell lung cancer and developed irAEs following ICI treatment. During ICI treatment, we conducted monthly measurements of the serum antibody levels in this patient, including those which were both tumor‐ (anti‐p53 antibody) and nonspecific (immunoglobulins). Anti‐p53 antibodies and IgM had not increased during ICI treatment, but the serum levels of IgG and IgA had gradually increased before the occurrence of irAEs. These results suggest that monitoring serum immunoglobulin levels might enable the early detection of ICI‐induced immune responses in patients with lung cancer. [ABSTRACT FROM AUTHOR]

Lung cancer remains the most common cause of cancer-related deaths in the United States. Traditional treatment of non-small cell lung cancer has included surgical resection for suitable candidates with early stage (I/II) disease and various chemoradiotherapeutic regimens used for advanced disease, for which prognosis has been poor. Since the early 2000s, there has been a revolution in the diagnosis and treatment of non-small cell lung cancer driven by improved diagnostic techniques and therapies targeted to druggable oncogenic drivers or manipulation of the immunologic milieu in the tumor microenvironment. With this has come a need for frequently updated comprehensive data regarding response to treatment and acquired resistance to targeted therapies. In this article, we aim to provide a concise review of the state-of-theart in lung cancer workup in 2021, with a focus on how molecular data now informs treatment decisions. With the burgeoning use of immunotherapeutic approaches, we will also discuss some of the complications seen, and briefly discuss their management. [ABSTRACT FROM AUTHOR]

Immunotherapy is increasingly defining a role in a wide variety of tumours such that as use becomes more ubiquitous, so too will the complications. A relatively rare complication of immunotherapy use is immune-related gastritis. In this case series, we present two cases of immunotherapy-related gastritis from our institution and undertake a comprehensive review and analysis of the literature around this less common adverse event. [ABSTRACT FROM AUTHOR]

The field of oncology has undergone rapid changes following the introduction of immunotherapies and biologics. However, these changes have also created new roles for radiology in both diagnosis and treatment. Our article addresses the evolving role of radiology in the immune checkpoint inhibitor era of oncology. With the progression of new immunotherapies for cancer, imaging paradigms and image guided therapy options have changed. Multidisciplinary oncology teams should be aware of these opportunities for collaboration. • The role of radiology in the immune checkpoint inhibitor era (ICI) of oncology continues to evolve • Radiologists are key to advancing imaging paradigms to support the management of patients receiving ICIs • Imaging is a key component of the diagnosis and management of immune related adverse events (irAEs) • Locoregional image-guided treatments may fill the gap between systemic and surgical treatment options for cancer [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs)—anti-programmed death-1 (PD-1) and their ligands (PD-L1 and PD-L2) have become widely used in the treatment of several malignancies. Many immune-related adverse events (irAEs) have been linked to these agents. Nonetheless, tuberculosis (TB) reactivation during their use is increasingly recognized and reported. Herein, we present a 58-year-old lady with advanced non-small cell lung cancer (NSCLC) ALK-negative, EGFR wild, and PD-L1 immune histochemistry (IHC) strongly positive in 95% of tumor cells, on ongoing treatment with Pembrolizumab as a first-line monotherapy. Our patient presented with 1-week history of productive cough and high-grade fever. Further workup yielded the diagnosis of pulmonary tuberculosis after her Pembrolizumab sixth cycle with positive AFB smear and TB PCR from BAL (rifampin resistance not detected), with negative HIV status. Hence, immunotherapy was held, and patient was commenced on anti-TB regimen. History revealed contact with active TB patient over the past decade, without previous documentation of latent TB or previous TB infection. Her sputum AFB smear remained persistently positive 4 weeks through anti-TB regimen course. Later, the patient was discharged after her sputum was cleared from AFB (two negative sets). In light of pembrolizumab mechanism of action as an immune checkpoint inhibitor, we suspected its implication on reactivating latent TB which was observed in our patient demonstrating features of pulmonary tuberculosis. She was not re-challenged with Pembrolizumab following TB diagnosis. [ABSTRACT FROM AUTHOR]

Background: Immune-related adverse events (iRAEs) are known complications of immune checkpoint inhibitors (ICIs). Early identification and management leads to improved morbidity and mortality. This study seeks to address our center's experience with iRAEs in the emergency department (ED). Methods: We performed a retrospective review of patients treated with ICIs in 2018 and 2019 for any indication. All diagnoses of iRAEs were recorded. For all patients who presented to the ED following administration of an ICI, we assessed whether the presenting symptoms were eventually diagnosed as an iRAE. We assessed disposition, time to initiation of corticosteroids and outcomes in these patients. Results: 351 evaluable patients were treated with an ICI, 129 patients (37%) had at least one presentation to the ED, 17 of whom presented with symptoms due to a new iRAE. New iRAE diagnoses were broad, occurred after median 2 cycles, majority irAEs were grade 3 or higher (70.6%), and two patients died due to toxicity. Twelve patients were admitted to the hospital during initial presentation or at follow-up, four required ICU care. All patients required immunosuppressive therapy, and only three were later re-challenged with an ICI. Of the patients who were admitted to the hospital, median time to first dose of corticosteroid was 30.5 h (range 1-269 h). Conclusions: Patients on ICI have a significant risk of requiring an ED visit. A notable proportion of iRAEs have their first presentation at the ED and often can present in a very nonspecific manner. A standardized approach in the ED at the time of presentation may lead to improved identification and management of these patients. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignancies. Toxicities of immunotherapy are variable, can involve almost every organ, therefore appropriate diagnosis and management of Immune Related Adverse Events (irAEs) is important. Immune-mediated pneumonitis is an uncommon, but potentially life-threatening toxicity of ICIs. Pre-existing lung disease, a history of lung radiotherapy, age >70 years and male gender are suggested as the risk factors of pneumonitis. Dyspnoea, dry cough, fever and chest pain are typical symptoms. Diagnostic algorithms recommend radiological investigation with a chest computed tomography scan. Additional diagnostic procedures - such as pulse oximetry, spirometry, measurement of carbon monoxide diffusing capacity, bronchoscopy with BAL may be helpful. The therapeutic approach is determined by the intensity of the symptoms and CT findings. Corticosteroids and antibiotics are the drugs of choice. Hospitalisation is necessary in severe cases, and other forms of immunosuppression (infliximab, mycophenolate mofetil) may be considered. Continuation of immunotherapy can be considered with caution in patients with G1-2 toxicity, when clinical improvement was achieved and steroids were tapered. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) have significantly driven the oncology treatment landscape as they immensely shift better clinical outcomes among various type of cancers. Challenges of using this approach are, without doubt, the immune related adverse events (IrAEs). These can have vital impact to affect multiple organs and some cases lead to fatality. Therefore, risk stratification should be cautiously taken into consideration while clinicians are dealing with ICIs. In this article, the risk factors from clinical trials or real-world reports that relevant to onset, level of severity, and particular type of IrAEs were discussed in order to promote IrAEs prompt attention in clinical practice. [ABSTRACT FROM AUTHOR]

IL‐6 is a cytokine that plays an important role in response to injury or infection and is a promising biomarker for predicting poor prognosis and therapeutic targets in non‐small cell lung cancer (NSCLC). This article reviews the biochemical mechanism, function and genotype of IL‐6, and summarizes the diagnostic and prognostic value of IL‐6 level. Anti‐IL‐6 therapy does not affect the effect of immunocheckpoint inhibitors (ICIs), but enhances its anticancer function, which may be the treatment option for immune‐related adverse events (irAEs) in the future. Therefore, IL‐6 may be a therapeutic target for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have been approved for clinical application in China. However, the increased immune-related adverse event (irAE) needs more attention. This review summarized the incidence, characteristic clinical manifestation and treatment of irAEs associated with programmed cell death protein-I (PD- l) and programmed cell death ligand-I (PD-LI) inhibitors. To have a deep insight into irAE, the potential mechanisms, the different incidences of cancer types, influencing factors and the direction of future research were also discussed here to provide guidance for clinical oncologist to identify and monitor irAE . [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFα) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFα and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFα and one or two ICIs. Case presentations: Five patients with different primary malignancies were treated with ipilimumab/ nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression. Conclusions: Concurrent treatment with anti-TNFα and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (CPIs) are an effective treatment for many cancers but cause diverse immune-related adverse events (IrAEs). Rheumatological IrAEs include arthralgia, arthritis, tenosynovitis, myositis, polymyalgia rheumatica and sicca syndrome. CPI use can unmask RA as well as causing flares of prior autoimmune or connective tissue disease. Oncologists categorize and grade IrAEs using the Common Terminology Criteria for Adverse Events and manage them according to international guidelines. However, rheumatological events are unfamiliar territory: oncologists need to work with rheumatologists to elicit and assess symptoms, signs, results of imaging and autoantibody testing and to determine the use of steroids and DMARDs. Myositis may overlap with myasthenic crisis and myocarditis and can be life-threatening. Treatment should be offered on balance of risk and benefit, including whether to continue CPI treatment and recognizing the uncertainty over whether glucocorticoids and DMARDs might compromise cancer control. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed death receptor-1/ligand-1 (anti-PD-1/anti-PD-L1) caused a breakthrough in oncology and significantly improved therapeutic outcomes in cancer patients. ICIs generate a specific reaction in T cells, directed against antigens on cancer cells, leading to their damage and death. Through similar or the same antigens, activated lymphocytes may also have a cytotoxic effect on healthy cells, causing development of specific adverse effects – so-called immune-related adverse events (irAEs). We present the case report of a 56 year old patient with disseminated melanoma. During treatment with immunotherapy (anti PD-1), neutropenic fever and pancytopenia occurred. Trepanobiopsy of the bone marrow was performed to determine the cause of pancytopenia. Histopathological assessment of bone marrow combined with immunophenotype investigations may explain the cause of hematological disorders occurring in the course of treatment with ICIs, and support the choice of an appropriate treatment, directly translated into positive outcomes. [ABSTRACT FROM AUTHOR]

In recent years, immune checkpoint inhibitors (ICIs) were successfully introduced to cancer therapy and these drugs have already become essential for the treatment of various non-curable tumors. Compared to conventional chemotherapy or tyrosine kinase inhibitors, ICIs generally exhibit a favorable side effect profile further promoting their increasing prescription rate. However, increasing use of these substance made clear that ICI induced activation of the immune system may also lead to immune-related adverse events (irAEs). Common irAEs are dermatological, gastrointestinal, or endocrine side effects but further tissue types and organ systems may also be affected. A detailed knowledge of these potential side effects is important as early recognition is the key to successful treatment, reversibility of organ dysfunction and in some cases even prevention of fatal outcome. In more severe irAEs, immunosuppression may be necessary to cope with these side effects. To increase awareness of irAEs and support immediate and successful management, we provide a comprehensive review on most common irAEs of ICIs, their diagnosis, and treatment. [ABSTRACT FROM AUTHOR]

• Serum cytokines and growth factors were assessed during nivolumab treatment. • Follistatin and IP-10 levels are associated with durable clinical benefit. • Levels of serum RANTES are associated with irAE onset. • Clinical benefit and irAEs are regulated by different immune mechanisms. Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers. Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated. Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-α levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p < 0.05) and RANTES was associated with irAE onset (p < 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE. Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors are used with increasing regularity in metastatic disease. Anti-CTLA4 (ipilimumab) anti-PD1 (pembrolizumab, nivolumab) or anti-PD-L1(avelumab, atezolizumab) are approved for use in metastatic melanoma, non-small cell lung cancer, renal cell carcinoma and other malignancies. Despite their advantages, their immune adverse reactions are important. This paper is a review current literature regarding rheumatologic adverse reactions that follow ICI treatment. Their frequency is not high but it is important to correctly diagnose and treat them. Most of the adverse reactions are mild and moderate. The treatment for immune related adverse events (IRAEs) is currently not supported by a sufficient amount of studies. The best treatment option is therefore based on the rheumatologist experience. [ABSTRACT FROM AUTHOR]

This letter describes the potential effect of B cell depletion on immune related adverse events associated with immune checkpoint inhibition. B cell depleting agents such as rituximab reduce B cell to plasma cell differentiation and antibody production. This treatment strategy is used in several immune mediated inflammatory diseases such as rheumatoid arthritis and small vessel vasculitis. The immune related adverse events associated with immune checkpoint inhibition resemble immune mediated inflammatory diseases. Here, we report a lower incidence of hypothyroidism in a trial of combined B cell depletion and immune checkpoint inhibitor treatment compared with studies of immune checkpoint inhibitor monotherapy. This letter aims to increase awareness of the immune related adverse events associated with immune checkpoint inhibition in future clinical trials of immune checkpoint inhibition together with B cell depletion (primarily trials of B cell lymphomas). Hopefully, observations from these clinical trials can guide future treatment strategies to treat or prevent immune related adverse events associated with immune checkpoint inhibition. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors are used with increasing regularity in metastatic disease. Anti-CTLA4 (ipilimumab) anti-PD1 (pembrolizumab, nivolumab) or anti-PD-L1(avelumab, atezolizumab) are approved for use in metastatic melanoma, non-small cell lung cancer, renal cell carcinoma and other malignancies. Despite their advantages, their immune adverse reactions are important. This paper is a review current literature regarding rheumatologic adverse reactions that follow ICI treatment. Their frequency is not high but it is important to correctly diagnose and treat them. Most of the adverse reactions are mild and moderate. The treatment for immune related adverse events (IRAEs) is currently not supported by a sufficient amount of studies. The best treatment option is therefore based on the rheumatologist experience. [ABSTRACT FROM AUTHOR]

Immune-related endocrine adverse events occur in up to one third of patients treated with immune checkpoint inhibitors. The purpose of this article is to provide a comprehensive review of the multimodality imaging features of the different immune-related endocrine adverse events. In this article, we will introduce the different types of immune checkpoint inhibitors used in clinical practice, and for each endocrine organ affected we will describe the clinical presentation, the multimodality imaging features at presentation and after treatment, and the possible differential diagnosis. [ABSTRACT FROM AUTHOR]

Background: Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab). Methods: A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R©, package meta. Results: Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72% (95% CI, 65-79%). The overall incidence of high-grade irAEs was 24% (95% CI, 18-30%). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61% (95% CI, 56-66%) for ipilimumab 3 mg/kg and 79% (95% CI, 69-89%) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86% of patients. The median time of onset of irAEs was about 10 weeks (IQR, 6-12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60% of patients. Conclusion: The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) is a relatively new disease entity caused by ICI agents during cancer therapy. Reactive arthritis (ReA) is a well-known disease entity caused by urogenital or gastrointestinal bacterial infection or pneumonia. In this sense, ICI-IA and ReA are both defined by a reaction to a well-specified causal event. As a result, comparing these diseases may help to determine therapeutic strategies. We compared ICI-IA and ReA with special focus on pharmacological management. Specifically regarding treatment, we conducted a literature search of studies published in the PubMed database. Inclusion criteria were studies on treatment with non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GC), or disease modifying antirheumatic drugs (DMARDs) in ICI-IA or ReA. During systematic selection, 21 studies evaluating ICI-IA and 14 studies evaluating ReA were included. In ICI-IA, prospective and retrospective studies have shown effects of non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoid (GC), sulfasalazine (SSZ), methotrexate (MTX), hydroxychloroquine (HCQ) and TNFi. In ReA, retrospective studies evaluated NSAIDs and GC. A randomized controlled trial reported the effect of SSZ, and a retrospective study reported the effect of MTX and SSZ in combination with tumor necrosis factor alpha inhibition (TNFi). For both entities, small case reports show treatment effects of interleukin 6 receptor inhibition (IL-6Ri). This literature review identified both similarities and differences regarding the pathogenesis and clinical features of ReA and ICI-IA. Studies on treatment reported effectiveness of NSAIDs, GC, MTX, SSZ and TNFi in both diseases. Further, small case reports showed effects of IL-6Ri. [Display omitted] • ICI-IA and ReA are both characterized by a synovial reaction to a well-defined causal event. • There were both similarities and differences in the clinical features of ReA and ICI-IA. • We reveal the efficacy of several csDMARDs and bDMARDs in both ReA and ICI-IA. • The potential for a self-limiting disease course is important for choice of treatment strategy. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) significantly improve the outcomes of patients with advanced clear cell renal cell carcinoma (ccRCC); however, high-grade toxicities can occur, particularly during combination therapy. Herein, we report a patient with advanced metastatic ccRCC, who developed grade 4 cholestasis during combined therapy with nivolumab and cabozantinib. After the exclusion of common disorders associated with cholestasis and a failure of corticosteroids (CS), a liver biopsy was performed that demonstrated severe ductopenia. Consequently, a diagnosis of vanishing bile duct syndrome related to TKI and ICI administration was made, resulting in CS discontinuation and ursodeoxycholic acid administration. After a 7-month follow-up, liver tests had returned to normal values. Immunological studies revealed that our patient had developed robust T-cells and macrophages infiltrates in his lung metastasis, as well as in skin and liver tissues at the onset of toxicities. At the same time, peripheral blood immunophenotyping revealed significant changes in T-cell subsets, suggesting their potential role in the pathophysiology of the disease. [ABSTRACT FROM AUTHOR]

The last 12 months have seen the beginning of a new era in the treatment options available for patients with metastatic cutaneous melanoma, a disease previously characterised by its poor prognosis and limited treatment options. Two mechanistically diverse agents have now demonstrated an overall survival benefit in different patient subgroups and further clinical trials are ongoing with emerging single agents and novel combinations. The first agent to demonstrate an overall survival benefit was the CTLA-4 antibody, ipilimumab, illustrating the importance of the immune system and immunomodulation in melanoma tumorigenesis. The second group of agents to show a survival benefit were the selective BRAF inhibitors, vemurafenib and GSK2118436, in patients who are BRAF V600 mutation positive. In addition, in the same BRAF mutant patient population, MEK inhibitors also show promising results and are currently under investigation in later stage trials. Although ipilimumab, BRAF and MEK inhibitors are just passing through the clinical trials arena, their use will rapidly become more widespread. Along with their significant clinical benefits, there are also unique adverse events related to these agents. Although the majority are mild and can be managed with supportive treatment, some toxicities require special management strategies. We outline up-to-date clinical development and management guidelines for ipilimumab, as well as the BRAF and MEK inhibitors. [ABSTRACT FROM AUTHOR]

The last 12 months have seen the beginning of a new era in the treatment options available for patients with metastatic cutaneous melanoma, a disease previously characterised by its poor prognosis and limited treatment options. Two mechanistically diverse agents have now demonstrated an overall survival benefit in different patient subgroups and further clinical trials are ongoing with emerging single agents and novel combinations. The first agent to demonstrate an overall survival benefit was the CTLA-4 antibody, ipilimumab, illustrating the importance of the immune system and immunomodulation in melanoma tumorigenesis. The second group of agents to show a survival benefit were the selective BRAF inhibitors, vemurafenib and GSK2118436, in patients who are BRAF V600 mutation positive. In addition, in the same BRAF mutant patient population, MEK inhibitors also show promising results and are currently under investigation in later stage trials. Although ipilimumab, BRAF and MEK inhibitors are just passing through the clinical trials arena, their use will rapidly become more widespread. Along with their significant clinical benefits, there are also unique adverse events related to these agents. Although the majority are mild and can be managed with supportive treatment, some toxicities require special management strategies. We outline up-to-date clinical development and management guidelines for ipilimumab, as well as the BRAF and MEK inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy and, in particular, immune checkpoint inhibitors (ICIs), have transformed non-small cell lung cancer treatment options. Although many patients are treated with ICIs, a large number do not respond. Thus, there is a need to identify biomarkers of response. In this study, we evaluated the value of multiple routinely collected variables (from metastatic sites to levels of several conventional peripheral blood parameters) as biomarkers of response to ICIs. Our data indicates that, although several characteristics are associated with response, many present strong interrelations, which should be taken into account when creating compendiums of biomarkers to maximize their predictivity. Finally, we describe a collection of characteristics (LDH levels, sex, and presence or absence of immune related adverse events) that, in our group of patients, had the best predictive value. Immune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment. Unfortunately, only some patients benefit from these therapies. Thus, certain clinicopathological characteristics of the patients have been proposed as biomarkers of ICIs response. We assembled a retrospective cohort of 262 NSCLC patients treated with ICIs, compiled relevant clinicopathological characteristics, and studied their associations with treatment outcome using Cox proportional-hazards survival models. Additionally, we investigated the interrelations between clinicopathological features and devised a method to create a compendium associated with ICIs response by selecting those that provide non-redundant information. In multivariate analyses, ECOG performance status (hazard ratio (HR) 1.37 (95% CI 1.11 to 1.68), p < 0.005), LDH (HR 1.24 (95% CI 1.03 to 1.48), p = 0.02)) and PD-L1 negativity were associated with decreased progression-free survival (PFS) (HR 1.92 (95% CI 1.03 to 3.58), p = 0.04), whereas presentation of immune-related adverse events (irAEs) (HR 0.35 (95% CI 0.22 to 0.55, p < 0.005) or females (HR 0.52 (95% CI 0.33 to 0.80, p < 0.005) had longer PFS. Additionally, numerous clinicopathological indicators were found to be interrelated. Thus, we searched for features that provide non-redundant information, and found the combination of LDH levels, irAEs, and gender to have a better association with ICIs treatment response (cross-validated c-index = 0.66). We concluded that several clinicopathological features showed prognostic value in our real-world cohort. However, some are interrelated, and compendiums of features should therefore consider these interactions. Joint assessment of LDH, irAEs, and gender may be a good prognostic compendium. [ABSTRACT FROM AUTHOR]

Improved anti-tumour responses under immune checkpoint inhibition (ICI) are associated with concomitant autoimmune disease development termed immune related adverse events (irAEs), of which approximately 5% are rheumatic in nature. Generally, oncologists and other specialists vigorously treat irAEs in spite of the generally accepted beneficial effect of irAEs on tumour survival. Herein, we highlight mechanistic insights on how tumour responses and certain types of autoimmunity appear to be inextricably linked around CD8+ T-cell mediated responses and that strategies that interfere with such shared immunopathgenesis could impact of survival. We discuss the possible circumstances in which intensive immunosuppressive therapy for irAEs that occur with ICIs might blunt anti-tumour immunity. We also discuss potential therapeutic strategies for emergent ICI related autoimmunity and propose some treatment considerations and research questions to minimize the impact of overzealous immunosuppression strategies on tumour responses. Thus, refraining from using powerful therapeutic armamentarium to treat irAEs, especially when these are not considered as life-threating might improve the prognosis of ICI therapy. [ABSTRACT FROM AUTHOR]

• Cancer immunotherapy revolutionize cancer treatment but is associated with unpredictable immune-related adverse events (irAEs). • The tumor microenvironment is complex and changeable and thus it may be one potential explanation for varies toxicities. • Toxicities of cancer immunotherapy are highly variable and mostly mild, but life-threatening cases have been reported. • Innocuous symptoms may herald potentially grade 3–4 toxicity; therefore, close attention must be paid to all patients. Immune checkpoint inhibitors (ICPIs) and chimeric antigen receptor (CAR) T-cell therapy are two main promising methods of immunotherapy, which have become increasingly important in cancer treatment. After the wider application of these medicine in clinic, a range of immune related adverse events (irAEs) covering almost any system arouse the concern for being randomness and unpredictability. Even if most adverse events are mild and controllable after thoughtful management, the occurrence of life-threatening toxicities should not be ignored because of the insidious and atypical symptoms, which makes the early diagnosis even more challenging. In this review, a brief introduction of immunotherapy and mechanisms underlying irAEs is involved. We mainly focus on the early diagnostic method and recommended management of toxicities of different systems separately, and consequently maximized effectiveness of immunotherapy can be achieved. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICPis) have revolutionised the treatment of melanoma by significantly increasing survival rates and disease control. However, ICPis can have specific immune-related adverse events, including rare but severe neurological toxicity. Case presentation: We report a 44-year-old man diagnosed with stage IIIB melanoma who developed metastatic disease (pulmonary and brain metastases) and was treated with stereotactic radiosurgery and nivolumab immunotherapy. He developed asymptomatic multifocal diffuse white matter lesions consistent with active central nervous system demyelination seen on brain MRI. One month after cessation of the immunotherapy, spontaneous regression of the demyelinating lesions was observed, suggesting a nivolumab-related toxicity. Conclusion: We report the first case of a melanoma patient with an asymptomatic and spontaneously reversible central nervous system demyelination following nivolumab immunotherapy. This case highlights the need for better recognition of such atypical and rare neurological toxicities which could be mistaken for progressive brain metastases. Early recognition and appropriate management are crucial to reduce severity and duration of these toxicities, especially for patients with less favourable evolution. [ABSTRACT FROM AUTHOR]

Ipilimumab, a monoclonal antibody targeting the cytotoxic T lymphocyte antigen-4 is a treatment option for metastatic melanoma. This receptor serves as an inhibitor receptor on T lymphocytes and blockage of these results predisposition to autoimmune diseases. The patients with autoimmune disorders were excluded in clinical trials and there is no sufficient data of the treatment on these patients who already have an autoimmune disorder. Here, we report a case of myasthenia gravis who was treated with ipilimumab and we presented the long-term prognosis of the patient after treatment. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFα) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFα and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFα and one or two ICIs. Case presentations: Five patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression. Conclusions: Concurrent treatment with anti-TNFα and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality. [ABSTRACT FROM AUTHOR]