BACKGROUND: Immune checkpoint inhibitors (ICIs) have promising clinical activity and are essential medications for patients with several malignancies. However, by deranging the immune system, these novel agents could lead to immune-related adverse events (IRAEs). Hepatotoxicity with checkpoint inhibitors usually results in acute hepatitis or drug-induced liver injury. METHODS: This review article discusses the recent clinical evidence available regarding checkpoint inhibitor-induced hepatitis and reviews an approach to their diagnosis and management. RESULTS: The rate of liver injury with ICIs varies between different checkpoint inhibitors. It has been reported that the incidence of various grades of autoimmune hepatotoxicity with CTLA-4 inhibitors is between 3%-9%. The clinical characteristics of ICIs-induced hepatotoxicity are quite heterogeneous but they are usually in line with an autoimmune induced liver injury. Management of severe ICIs-related hepatitis should consist of termination of the ICI and treatment with corticosteroids. CONCLUSION: ICIs have improved patients’,outcomes with different forms of malignancy,however, ICIs-related liver damage is a clinically significant entity in these patients. All patients should be monitored carefully for IRAEs while undergoing treatment with ICIs.

Brain metastasis (BM) is a common form of cancer that affects the central nervous system and has a significant impact on the life expectancy and quality of patients. Despite conventional treatments like surgery, chemotherapy, and radiotherapy, managing BM is challenging, and success rates are low. Immune checkpoint inhibitors (ICIs) have emerged as promising new therapies for advanced cancers and work by reversing the immune-evasive characteristics of tumor cells. ICIs have shown efficacy in various malignancies, prompting researchers to evaluate their efficacy in BM. Previously, the exclusion of BM patients from clinical trials was common due to the brain's immune-privileged nature. However, recent studies have demonstrated immune cell trafficking in and out of the brain, leading to several studies investigating the ICIs' application in BM patients. This study aimed to provide further evidence supporting the beneficial effects of ICIs in treating BM, as evidenced by improved response duration and survival time.

The importance of the gut microbiota in human health and disease has been known for a long time. Current investigations involving preclinical and clinical studies have presented numerous lines of evidence indicating that gut microbiota can influence the effectiveness of cancer immunotherapies, particularly immune checkpoint inhibitors (ICIs). The gut microbiota can alter the immune response in the tumor microenvironment (TME) by engaging with innate and adaptive immune cells. Notably, one of the primary methods by which the gut microbiota modulates antitumor immunity is through the production of metabolites, which are small molecules capable of traveling from the gut to other parts of the body and influencing local and systemic antitumor immune responses. This exploration of mechanisms has yielded valuable insights for developing microbiota-based therapeutic strategies such as fecal microbiota transplantation (FMT), probiotics, engineered microbiomes, and specific microbial metabolites. In this review, we explored several possible interventions that could enhance the efficacy of ICIs, thereby potentially restoring or augmenting patient responses to these therapeutic agents.

Purpose: To quantify the risk of ocular adverse events with immune checkpoint inhibitors (ICIs) as reported to the Food and Drug Administration (FDA). Methods: Disproportionality analysis using data from U. S. FDA's Adverse Events Reporting System (FAERS) database 2003 to 2018. Data from pharmaceutical manufacturers, healthcare providers, consumers in the U. S., and post-marketing clinical trial reports from U. S. and non-U. S. studies. All cases of uveitis, dry eye syndrome, ocular myasthenia and eye inflammation with use of the following ICIs: atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab and pembrolizumab. Reported odds ratios (RORs) and corresponding 95% confidence intervals (CIs) were computed for all drugs as a group or as individual agents. Results: We identified 113 ocular adverse events for all ICIs of interest including uveitis, dry eye, ocular myasthenia and eye inflammation. Nivolumab had the highest number of adverse events (N ¼ 68) associated with use of the ICI. Nivolumab had the highest association with ocular myasthenia [ROR ¼ 22. 82, 95% CI (7. 18e72. 50)] followed by pembrolizumab [ROR ¼ 20. 17, 95% CI (2. 80e145. 20)]. Among all ICIs approved in North America, atezolizumab had the highest association with eye inflammation [ROR ¼ 18. 89, 95% CI (6. 07e58. 81)] and ipilmumab had the highest association with uveitis [ROR ¼ 10. 54, 95% CI (7. 30e15. 22)]. Conclusion: The results of this disproportionality analysis suggest use of ICIs is associated with an increase risk for ocular adverse reactions. Future epidemiologic studies are needed to better quantify these adverse events.

Non-Small Cell Lung Cancer (NSCLC) patients undergoing Immune Checkpoint Inhibitors (ICIs) therapy exhibit diverse clinical outcomes. The Lung Immune Prognostic Index (LIPI) may emerge as a potential prognostic marker. This study systematically reviews and meta-analyzes the prognostic value of LIPI in predicting the clinical efficacy of ICIs therapy for NSCLC patients. A thorough literature review was performed using the Cochrane Library, Web of Science, PubMed, and Embase, following PRISMA guidelines. Studies assessing LIPI’s predictive value in NSCLC patients treated with ICIs were included. Effect sizes were aggregated utilizing a fixed-effects model. The studies featured in the review were appraised using the Newcastle-Ottawa Scale for quality assessment. Eight studies were incorporated into the meta-analysis, encompassing various treatment lines and ICIs. No substantial heterogeneity was detected across the studies. The meta-analysis revealed that the low-risk group exhibited significantly extended overall survival (OS) (HR=3.18, 95%CI: 2.78~3.59 and progression-free survival (PFS) (HR=1.60, 95%CI: 1.4~61.74, underscoring the predictive significance of LIPI for NSCLC patients treated with ICI therapy. No significant publication bias was detected. LIPI demonstrates potential as a prognostic marker for NSCLC patients receiving ICI therapy, contributing to the development of therapeutic strategies. Further prospective researches are required to investigate its relationship with factors such as tumor mutational burden, PD-L1 and PD-1.

Background: Immune checkpoint inhibitors (ICIs), including antiprogrammed cell death receptor-1, antiprogrammed cell death ligand-1, and anticytotoxic T-lymphocyte-antigen 4, have improved patients’ outcome in advanced malignancies. These agents are associated with immune-related adverse events, including skin toxicity, gastrointestinal toxicity, hepatotoxicity, renal toxicities, and endocrinopathies.Method: We retrospectively reviewed the electronic medical records of patients treated with ICIs for advanced malignancies from two tertiary cancer care centers in the Emirate of Dubai, United Arab Emirates (UAE), including Dubai Hospital and American Hospital from November 2015 to January 2019. The patients were identified through the hospital cancer registry. We retrospectively collected data regarding the subjects’ demographics, cancer type, type of ICIs, thyroid-related adverse events, and duration of treatment.Results: In the present paper, 43 patients received ICI and 19 (44%) developed thyroid dysfunctions. The median age of ICI-receiving subjects was 60 (27-80) years; 26 of them were male and 17 were female. Pembrolizumab was the most used agent (42%). Pretreatment thyroid functions were normal for all the patients. Following treatment initiation, 19 (44%) patients developed thyroid abnormalities, including overt hypothyroidism (n = 11, 57%), overt hyperthyroidism (n = 2, 11%), subclinical hypothyroidism (n = 4, 21%), and subclinical hyperthyroidism (n = 2, 11%). Thyroid abnormalities developed in 56% of them treated with Pembrolizumab and 37% treated with Nivolumab.Conclusion: Hypothyroidism was the most prevalent thyroid adverse event in the patients treated with ICIs in our study and the majority of thyroid dysfunction encounters took place in the first 6 weeks after ICI initiation. The treatment was well tolerated and there were no treatment-related discontinuations or deaths.

Background: Hepatocellular carcinoma (HCC) is characterized by high morbidity and mortality rates around the world, ranking the sixth most common malignant tumor and the second cause of cancer-related mortality. Most patients are diagnosed in the advanced stage, and therefore, there are limited therapeutic options. Transarterial chemoembolization (TACE), anti-angiogenic therapy, and immune checkpoint inhibitors (ICIs) are the research hotspots in HCC treatment. Objectives: This study aimed to explore the treatment effi, cacy and safety of TACE for refractory HCC patients after anti-angiogenic therapy combined with ICIs. Patients and Methods: In this study, patients with HCC, who progressed after anti-angiogenic therapy combined with ICIs, were included from July 2019 to October 2022. The progression-free survival (PFS) was evaluated by the Kaplan-Meier method, and the tumor response was determined based on the modifi, ed immune response evaluation criteria in solid tumors (iRECIST). The Common Terminology Criteria for Adverse Events version 5. 0 were also used to assess the adverse events. Results: A total of 34 patients were evaluated in this study, with a median PFS of fi, ve months (95% CI: 3. 7 months, 6. 3 months). The univariate analysis suggested that the level of aspartate aminotransferase was signifi, cantly associated with PFS (P < 0. 05). The objective response rates within three and six months were 26. 4% and 14. 6%, and the disease control rates were 58. 8% and 55. 9%, respectively. During the follow-up, one or more types of adverse events were reported in 10 (58. 8%) patients after treatment with atezolizumab and bevacizumab, while severe adverse events beyond grade III did not occur in any of the patients. Conclusion: The TACE may improve the survival of HCC patients, whose disease progresses after anti-angiogenic therapy combined with ICIs. However, the lack of a control group is one of the limitations of this study.

Dear Editor, To establish effective vaccines and developing appropriate therapeutic interventions in COVID-19, a full understanding of the immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical. The host immune system is dramatically perturbed by SARS-CoV-2 infection and the integrity of the host’, s homeostatic response plays an important role in the pathogenesis of COVID-19 (1). Immune checkpoint inhibitors (ICIs) are suggested to play an important role in the pathogenesis COVID-19 disease. ICIs have been used extensively in the treatment of cancers where they upregulate the host immune response against cancer cells. Important side effects include pneumonitis (2). Programed cell dead-1 (PD-1) is an important target of ICIs as it inhibits immune cell functions and is an exhaustion marker for immune cells. PD-1 is expressed on activated CD8+ T cells, B cells and NK cells in the setting of chronic antigen exposure. Binding of PD-1 and its ligand PD-L1 or PD-L2 on host tissues leads to the inhibition of T cell receptor (TCR) signaling and CD28 costimulation (3, 4). In chronic infections disease, PD-1 is expressed in exhausted TCD8 cells following demethylation of its promoter allowing DNA binding and gene activation by the FOXO1 transcription factor (5). In cancer, due to increasing the tumor cells changes and tumorigenic pattern, PD-1 expression is enhanced by activation of the c-FOS subunit of AP-1 (6). Aberrant PD-1 expression and activity, as a regulator of the immune response, may have both a beneficial and harmful impact on the immune system during cancer pathogenesis (7). . .

Context: Serum alpha-fetoprotein (AFP) has been shown to be valuable in tumor staging and predicting survival outcomes. In this investigation, we conducted a retrospective cohort analysis and a meta-analysis to assess the predictive significance of initial AFP levels in patients with hepatocellular carcinoma (HCC) who underwent treatment with immune checkpoint inhibitors (ICIs). Methods: We searched databases from inception until 14 July 2024 to identify cohort studies involving ICI treatments in HCC patients with baseline AFP data. We also retrospectively analyzed patients with HCC treated with ICIs to assess the therapeutic effect in the high AFP (AFP ≥ 400 ng/mL) group and the low AFP (AFP < 400 ng/mL) group in terms of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: In the meta-analysis, a total of 34 studies, comprising 8,799 patients, were included, while the retrospective cohort study encompassed 55 patients. In the meta-analysis, the summarized hazard ratios (HRs) of AFP ≥ 400 ng/mL versus AFP < 400 ng/mL for ICI therapy indicated that the high AFP group had a poorer outcome compared to the low AFP group, with a pooled HR for OS of 1.69 (95% CI: 1.57 - 1.82, P < 0.001) and a pooled HR for PFS of 1.47 (95% CI: 1.33 - 1.63, P < 0.001). In the retrospective cohort study, higher AFP levels were associated with a lower DCR for ICIs, with a DCR of 42.9% in the high AFP group and 77.8% in the low AFP group (P = 0.008). Cox model analysis showed that higher serum AFP was an independent predictor for shorter OS (HR 3.584, 95% CI: 1.466 - 8.762, P = 0.005). The toxicity analysis also displayed a strong association between high AFP and the occurrence of immune-related adverse events (irAEs) (P = 0.008). Conclusions: Higher serum AFP is associated with poorer efficacy of ICI treatment in HCC patients.