Immune checkpoint inhibitors (ICIs) have been approved to treat a variety of malignancies, including melanoma, improving the prognosis of these patients. However, they also cause a wide spectrum of rare immune-related adverse events (irAEs), not well-described yet. Although many endocrinopathies have been recognized as irAEs, primary hypoparathyroidism has rarely been reported, and thus clinical suspicion remains low. Herein, we describe the case of a 68-year-old female patient with metastatic melanoma who was admitted to the emergency department with acute symptomatic hypocalcemia due to immune-related (ir)-hypoparathyroidism after 2 cycles of nivolumab/ipilimumab. The patient was treated symptomatically, and her calcium levels were normalized. Parathyroid hormone levels were partially restored during the 6 months of follow-up. A literature review was conducted, summarizing all other subjects who developed ir-hypoparathyroidism after exposure to ICI-based regimen. The review identified 10 additional cases of hypoparathyroidism during immunotherapy. Interestingly, all melanoma cases with ir-hypoparathyroidism had received nivolumab/ipilimumab; 3 of them were also screened and detected with positive calcium-sensing receptor (CaSR) antibodies. Primary hypoparathyroidism may acutely manifest with symptomatic hypocalcemia and care providers should be aware of this rare irAE.

Immune-related adverse events typically occur during the early phases of immune checkpoint inhibitor therapy. However, late-onset immune-related adverse events can still arise long after the immune checkpoint inhibitor therapy has ended. Immune checkpoint inhibitor-related pneumonitis warrants special attention for risk assessment and early detection due to its potential for serious outcomes, including hospitalization and death. Despite its rarity, late-onset immune checkpoint inhibitor-related pneumonitis should be considered in the differential diagnosis for dyspnea in patients with a history of immune checkpoint inhibitor therapy to prevent morbidity and mortality. In this case report, we present a case of an 84-year-old female patient suffering from locally advanced triple-negative breast cancer and late-onset immune checkpoint inhibitor-related pneumonitis requiring hospitalization 104 days after the last cycle of pembrolizumab. Following successful treatment of late-onset immune checkpoint inhibitor-related pneumonitis with corticosteroids, a recurrence of immune checkpoint inhibitor-related pneumonitis occurred a month later. Corticosteroid therapy was reinitiated, gradually tapered after radiological improvement, and eventually discontinued. The patient remains in remission from breast cancer. For patients with a history of immune checkpoint inhibitor therapy, medical vigilance, accurate diagnosis, and timely management of late-onset immune checkpoint inhibitor-related pneumonitis are crucial.

The use of immune checkpoint inhibitors (ICIs) is increasing. Little is known about the frequency of late-onset immune-related adverse events (irAEs) and the patient-specific risk factors associated with their development.

To assess the incidence of persistent or de novo late-onset irAEs requiring hospitalization and identify patient factors associated with risk of late-onset irAEs.

This retrospective observational cohort study conducted from January 2011 to October 2022 included patients who received ICIs and were hospitalized with irAEs at an academic medical center. Exclusion criteria included ICI therapy outside of the hospital system and no irAE diagnosis during admission. Data were analyzed from November 15, 2022, to January 8, 2025.

Late-onset irAEs.

The main study outcomes were (1) incidence of irAE hospitalization at 0 to 6 months (early), more than 6 to 12 months (intermediate), and more than 12 months (late) after ICI initiation and (2) patient factors associated with risk of late-onset irAEs.

Among the 795 patients hospitalized with irAEs, the median age was 67.3 years (IQR, 58.3-74.8 years); 476 (59.9%) were male. Most patients (n = 517 [65.0%]) received anti-programmed death ligand 1 (PD-L1) and anti-programmed cell death 1 monotherapy, with the most common indications being melanoma (n = 335 [42.1%]) and lung cancer (n = 167 [21.0%]). The median time from start of ICI therapy to hospital admission was 2.7 months (IQR, 1.2-6.1 months), with 14.7% of patients (n = 117 of 795) presenting 6 to 12 months after initial ICI exposure and 10.8% of patients (86 of 795) presenting more than 12 months after initial exposure. The irAEs most likely to present late included those involving the kidney (10 of 32 [31.3%]) and hematologic (5 of 23 [21.7%]) organ systems. In univariate analysis, ICI type was significantly associated with the timing of hospital admission for irAEs; of the 517 patients receiving anti-PD-L1-based therapy, 13.5% (n = 70) presented late compared with 5.4% (9 of 167) receiving dual therapy with anti-cytotoxic T-lymphocyte-associated protein 4 (P < .001). Patients receiving perioperative ICI therapy were significantly more likely to be admitted at the intermediate interval (16 of 68 [23.5%]) compared with those with metastatic disease (87 of 678 [12.8%]) (P = .03). Timing of irAE was also significantly associated with active ICI exposure; among the patients presenting late, 7.4% (48 of 651) had received ICI therapy within the last 60 days compared with 26.4% (38 of 144) who had not had recent ICI exposure (P < .001).

The findings of this retrospective observational cohort study suggest that late irAEs are possible, with a subset of patients presenting years after the start of ICI therapy. Clinicians must remain vigilant for irAEs regardless of elapsed time from ICI therapy, especially as patients live longer and ICIs become more widely used. Future investigations are needed to better understand the risk factors for late-onset irAEs and the distinct immunologic pathways that underlie such events.

Immune-related adverse events (irAE) pose challenges to the use of immune checkpoint inhibitors (ICI). While risk factors for irAE are emerging, most studies are small, retrospective analyses that seldom report on diverse cancers or rare irAE. This paper reports a systematic review that summarises literature on irAE risk factors across cancers and proposes a categorisation approach.

A systematic search was conducted in Medline OVID, Embase and Web of Science databases following PRISMA guidelines (CRD42022310127). Original research published in peer-reviewed journals between January 2017-Decmeber 2021 were selected. Eligible studies included patients with any cancer and evaluated any potential risk factor for any grade/type of irAE. Study design, sample size, and method for analysing association between irAE and risk factors were compared.

A total of 293 eligible studies containing 305,879 patients receiving ICI reported irAE in 58,291 patients (19.1 %). There were 221 retrospective, 55 prospective studies, and 17 systematic reviews/meta-analyses. Eighteen studies evaluated the predictive validity of models. Proposed risk factors were grouped based on common themes and underlying aetiology: 1) patient, 2) laboratory, 3) medical history, 4) cancer-related, 5) clinical score, 6) medications, and 7) imaging features. Opposing associations were reported between advancing age and irAE risk.

This systematic review provides a comprehensive overview of evidence on irAE risk factors across a large patient population. Studies were heterogeneous resulting from variations in design, sample size and analysis method, and lack generalisability due to statistically underpowered evidence. We propose an approach to categorise potential irAE risk factors to support ongoing collaborative research.

Background/Objectives: Earlier detection of severe immune-related hematological adverse events (irHAEs) in cancer patients treated with a PD-1 or PD-L1 inhibitor is critical to improving treatment outcomes. The study aimed to develop a simple machine learning (ML) model for predicting irHAEs associated with PD-1/PD-L1 inhibitors. Methods: We utilized the Observational Medical Outcomes Partnership-Common Data Model based on electronic medical records from a tertiary (KHMC) and a secondary (KHNMC) hospital in South Korea. Severe irHAEs were defined as Grades 3-5 by the Common Terminology Criteria for Adverse Events (version 5.0). The predictive model was developed using the KHMC dataset, and then cross-validated against an independent cohort (KHNMC). The full ML models were then simplified by selecting critical features based on the feature importance values (FIVs). Results: Overall, 397 and 255 patients were included in the primary (KHMC) and cross-validation (KHNMC) cohort, respectively. Among the tested ML algorithms, random forest achieved the highest accuracy (area under the receiver operating characteristic curve [AUROC] 0.88 for both cohorts). Parsimonious models reduced to 50% FIVs of the full models showed comparable performance to the full models (AUROC 0.83-0.86, p > 0.05). The KHMC and KHNMC parsimonious models shared common predictive features including furosemide, oxygen gas, piperacillin/tazobactam, and acetylcysteine. Conclusions: Considering the simplicity and adequate predictive performance, our simplified ML models might be easily implemented in clinical practice with broad applicability. Our model might enhance early diagnostic screening of irHAEs induced by PD-1/PD-L1 inhibitors, contributing to minimizing the risk of severe irHAEs and improving the effectiveness of cancer immunotherapy.

Transforming growth factor-β (TGF-β) superfamily plays an important role in tumor progression and metastasis. Activin A receptor type 1C (ACVR1C) is a TGF-β type I receptor that is involved in tumorigenesis through binding to different ligands.

To evaluate the correlation between single nucleotide polymorphisms (SNPs) of ACVR1C and susceptibility to esophageal squamous cell carcinoma (ESCC) in Chinese Han population.

In this hospital-based cohort study, 1043 ESCC patients and 1143 healthy controls were enrolled. Five SNPs (rs4664229, rs4556933, rs77886248, rs77263459, rs6734630) of ACVR1C were assessed by the ligation detection reaction method. Hardy-Weinberg equilibrium test, genetic model analysis, stratified analysis, linkage disequilibrium test, and haplotype analysis were conducted.

Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC, and those with rs77886248 TA mutant were related with higher risk, especially in older male smokers. In the haplotype analysis, ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC, while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC.

ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC, which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.

Immune-related adverse events (irAEs) induced by immune checkpoint inhibitors are difficult to predict and can lead to severe events. Although it is important to develop strategies for the early detection of severe irAEs, there is a lack of evidence on irAEs associated with ipilimumab plus nivolumab therapy for metastatic renal cell carcinoma (RCC). Therefore, this study aimed to investigate the association between eosinophil and severe irAEs in patients receiving ipilimumab plus nivolumab therapy for RCC.

In this retrospective study, 161 patients receiving ipilimumab plus nivolumab therapy for RCC were divided into three groups based on whether they experienced

Results

Although the eosinophil in the baseline samples did not differ between the severe irAE and non-irAE groups (2.8% vs. 2.5%, P = 0.75), regarding the 2-week samples, the eosinophil was significantly higher in the severe irAE group (mean, 6.6% vs. 3.3%; P < 0.05). Multivariate analysis showed that an eosinophil of ≥3.0% was a risk factor for severe irAEs (odds ratio, 6.01). Median progression-free survival (mPFS), mPFS from the start of ipilimumab plus nivolumab therapy to second-line therapy (mPFS2), and median overall survival (mOS) were the shortest in the non-irAE group. Although the mPFS did not differ between the severe and non-severe irAE groups (9.2 vs 14.2 months, P = 0.45), notably, mPFS2 and mOS in the former group tended to be shorter than those in the latter group (mPFS2: 29.2 vs not reached, P = 0.10; mOS: 36.9 vs 52.3 months, P = 0.06).

Discussion

An increased eosinophil 2 weeks after ipilimumab plus nivolumab therapy may be a predictor of severe irAEs, which are associated with poor prognoses, compared with non-severe irAEs among patients with RCC. We provide a novel rationale for the importance of monitoring eosinophil counts for the early detection of severe irAEs.

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Immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) are a treatment-limiting barrier. There are few large-scale studies that estimate irAE prevalence. This paper presents a systematic review that reports the prevalence of irAE by cancer type and ICI.

A systematic review was undertaken in MEDLINE OVID, EMBASE and Web of Science databases from 2017-2021. A total of 293 studies were identified for analysis and, of these, event rate was calculated for 272 studies, which involved 58,291 patients with irAE among 305,879 total patients on ICI. Event rate was calculated by irAE and ICI type.

Mean event rate for general irAE occurrence across any grade was 40.0% (37.3-42.7%) and high grade was 19.7% (15.8-23.7%). Mean event rates for six specific types of irAE are reported. Mean event rate for ICI monotherapy was 30.5% (28.1-32.9%), 45.7% (29.6-61.7%) for ICI combination therapy, and 30.0% (25.3-34.6%) for both ICI monotherapy and combination therapy.

This systematic review characterises irAE prevalence across current research that examines irAE risk factors across cancers and ICI. The findings confirms that irAE occurrence is very common in the real-world setting, both high grade and irAE across any grade.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block inhibitors of T cell activation and function. With the widespread use of ICIs in cancer therapy, immune-related adverse events (irAEs) have gradually emerged as urgent clinical issues. Tumors not only exhibit high heterogeneity, and their response to ICIs varies, with "hot" tumors showing better anti-tumor effects but also a higher susceptibility to irAEs. The manifestation of irAEs displays a tumor-heterogeneous pattern, correlating with the tumor type in terms of the affected organs, incidence, median onset time, and severity. Understanding the mechanisms underlying the pathogenic patterns of irAEs can provide novel insights into the prevention and management of irAEs, guide the development of biomarkers, and contribute to a deeper understanding of the toxicological characteristics of ICIs. In this review, we explore the impact of tumor type on the therapeutic efficacy of ICIs and further elucidate how these tumor types influence the occurrence of irAEs. Finally, we assess key candidate biomarkers and their relevance to proposed irAE mechanisms. This paper also outlines management strategies for patients with various types of tumors, based on their disease patterns.

Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment by enhancing the immune response against tumor cells. However, their influence on immune pathways can lead to immune-related adverse events such as pneumonitis, necessitating rapid diagnosis and management to prevent severe complications. These adverse events arise from the activation of the immune system by immunotherapeutic drugs, leading to immune-mediated inflammation and tissue damage in various organs and tissues throughout the body. The present review article discusses the pathophysiology, clinical presentation, diagnostic modalities and management strategies for ICI-related pneumonitis, emphasizing early recognition and tailored interventions. Future research endeavors should focus on elucidating the underlying mechanisms of pneumonitis and identifying predictive biomarkers to guide personalized treatment strategies in this evolving field of oncology.

The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented.

Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants were tested for association with ILICI risk compared to the general population and other DILI controls.

The 57 high-causality cases were attributed to pembrolizumab (16), ipilimumab (15), ipilimumab and nivolumab (13), and other immune checkpoint inhibitors (13) and occurred at a median of 72 days after the first infusion. Median age was 57.8 years, 66% male, and 89% were non-Hispanic Whites. At DILI onset, 53% had hepatocellular, 35% mixed, and 15% cholestatic, with younger patients more likely to have hepatocellular injury. The incidence of ANA, smooth muscle antibody, and elevated IgG levels was low (17%, 23%, and 0%), but corticosteroids were given to 86%. Microgranulomas and hepatic steatosis were seen in 54% and 46% of the 26 liver biopsies, respectively. The HLA alleles associated with autoimmune hepatitis were not over-represented, but 2 host immune response genes (EDIL3 and SAMA5A) and 3 other genes (GABRP, SMAD3, and SLCO1B1) were associated with ILICI (OR: 2.08-2.4, p<0.01).

ILICI typically arises within 12 weeks of initiating immunotherapy and is self-limited in most cases. Genetic variants involved in host T-cell regulation and drug disposition were identified, implicating these pathways in the pathogenesis of ILICI. If validated, these findings could lead to improved diagnostic instruments and possible treatments for ILICI.

Immune checkpoint inhibitors (ICIs) constitute a pivotal class of immunotherapeutic drugs in cancer treatment. However, their widespread clinical application has led to a notable surge in immune-related adverse events (irAEs), significantly affecting the efficacy and survival rates of patients undergoing ICI therapy. While conventional hematological and imaging tests are adept at detecting organ-specific toxicities, distinguishing adverse reactions from those induced by viruses, bacteria, or immune diseases remains a formidable challenge. Consequently, there exists an urgent imperative for reliable biomarkers capable of accurately predicting or diagnosing irAEs. Thus, a thorough review of existing studies on irAEs biomarkers is indispensable. Our review commences by providing a succinct overview of major irAEs, followed by a comprehensive summary of irAEs biomarkers across various dimensions. Furthermore, we delve into innovative methodologies such as machine learning, single-cell RNA sequencing, multiomics analysis, and gut microbiota profiling to identify novel, robust biomarkers that can facilitate precise irAEs diagnosis or prediction. Lastly, this review furnishes a concise exposition of irAEs mechanisms to augment understanding of irAEs prediction, diagnosis, and treatment strategies.

The advent of immune checkpoint inhibitors (ICIs) in cancer treatment has marked a transformative era, albeit tempered by immune-related adverse events (irAEs), including those impacting the musculoskeletal system. The lack of precise epidemiologic data on rheumatic irAEs is attributed to factors such as potential underrecognition, underreporting in clinical trials, and the tendency to overlook manifestations without immediate life-threatening implications, further complicating the determination of accurate incidence rates, while the complete understanding of the mechanisms driving rheumatic irAEs remains elusive.

This literature review comprehensively examines rheumatic irAEs in cancer patients undergoing ICI therapy, encompassing epidemiology, risk factors, mechanisms, clinical manifestations, and current management guidance for prevalent conditions such as inflammatory arthritis, polymyalgia rheumatica, and myositis. Less frequent rheumatic and musculoskeletal irAEs are also explored, alongside insights into ongoing clinical trials testing therapeutic and preventive strategies for irAEs. A thorough literature search on Medline and the National Cancer Institute Clinical Trials Database was conducted up to October 2023 to compile relevant information.

In light of the evolving landscape of cancer immunotherapy, there is a compelling need for prospective longitudinal studies to enhance understanding and inform clinical management strategies for rheumatic irAEs.

The knowledge surrounding the application of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers is continuously expanding and evolving. These therapies work by enhancing the body's natural immune response against tumors, which may have been suppressed by certain pathways. The effectiveness of ICIs in treating adult cancers has been widely acknowledged. However, the results of early phase I/II clinical trials that exclusively targeted the use of ICIs for treating different pediatric cancers have been underwhelming. The response rates to ICIs have generally been modest, except for cases of pediatric classic Hodgkin lymphoma. There seems to be a notable disparity in the immunogenicity of childhood cancers compared to adult cancers, potentially accounting for this phenomenon. On average, childhood cancers tend to have significantly fewer neoantigens. In recent times, there has been a renewed sense of optimism regarding the potential benefits of ICI therapies for specific groups of children with cancer. In initial research, individuals diagnosed with pediatric hypermutated and SMARCB1-deficient cancers have shown remarkable positive outcomes when treated with ICI therapies. This is likely due to the underlying biological factors that promote the expression of neoantigens and inflammation within the tumor. Ongoing trials are diligently assessing the effectiveness of ICIs for pediatric cancer patients in these specific subsets. This review aimed to analyze the safety and effectiveness of ICIs in pediatric patients with different types of highly advanced malignancies.

The aim is to summarize the latest data on the incidence, clinical manifestations, and management of immune- mediated liver injury from checkpoint inhibitors (ILICI).

ILICI develops in 10-15% of oncology patients receiving immunotherapy with most having asymptomatic serum aminotransferase and/or alkaline phosphatase elevations. Most grade 1-2 ILICI patients improve with drug discontinuation and/or short-term oral corticosteroids. In contrast, the 2-3% with grade 3/4 hepatotoxicity frequently require oral or intravenous corticosteroids and some are hospitalized to initiate further immunosuppression with mycophenolate mofetil or azathioprine. Liver biopsy is generally reserved for patients with atypical features or those with severe hepatotoxicity who fail to respond to treatment. Up to 3% of ILICI patients with a cholestatic profile have MRI evidence of intra or extrahepatic cholangitis that responds poorly to immunosuppression. Most ILICI patients improve during follow-up and liver-related death is very uncommon (<1%). Up to 30% of rechallenged ILICI patients develop recurrent hepatotoxicity with a shorter latency.

ILICI is increasingly encountered by gastroenterologists evaluating oncology patients with abnormal liver biochemistries. A stepwise approach to exclude viral hepatitis, alcohol, hepatic metastases, and pancreaticobiliary disease is recommended. The majority of ILICI patients fully recover with ICI discontinuation and short-term corticosteroids or a second line immunosuppressant.

The introduction of immune checkpoint inhibitors (ICIs) has transformed the management of various malignancies. Alongside their therapeutic success, the widespread application of ICIs has unveiled a spectrum of immune-related adverse events (irAEs), most often affecting the skin. Cutaneous irAEs (cirAEs) encompass a range from common morbilliform and lichenoid rashes to more severe conditions such as bullous dermatoses and psoriasiform eruptions, each presenting distinct clinical challenges. Moreover, less common but clinically severe cutaneous reactions like toxic epidermal necrolysis have also been observed. cirAEs are frequently observed, with an incidence ranging from 37% to 70% for anti-cytotoxic T lymphocyte-associated antigen-4 antibodies and 17% to 40% for anti- programmed death-1/anti-programmed death ligand-1 antibodies. Recognizing the critical need for effective therapeutic strategies, this review carefully examines current approaches and guidelines for managing cirAEs.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Although immune checkpoint inhibitors have greatly improved cancer therapy, they also cause immune-related adverse events, including a wide range of inflammatory side effects resulting from excessive immune activation. Types of immune-related adverse events are diverse and can occur in almost any organ, with different frequencies and severities. Furthermore, immune-related adverse events may occur within the first few weeks after treatment or even several months after treatment discontinuation. Predictive biomarkers include blood cell counts and cell surface markers, serum proteins, autoantibodies, cytokines/chemokines, germline genetic variations and gene expression profiles, human leukocyte antigen genotype, microRNAs and the gut microbiome. Given the inconsistencies in research results and limited practical utility, there is to date no established biomarker that can be used in routine clinical practice, and additional investigations are essential to demonstrate efficacy and subsequently facilitate integration into routine clinical use.

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.

Extensive investigations have been conducted regarding the potential correlation between blood type and the immune system, as well as cancer risk in the Southern Chinese population. However, the prognostic value of the blood group and its genetic determinants in the context of immune checkpoint inhibitor (ICI) treatment remains unclear. Therefore, the associations between the ABO blood group and its single nucleotide polymorphisms (SNPs) were examined in relation to ICI treatment outcomes in 370 eligible patients with cancer. This approach allowed us to derive the blood group from the SNPs responsible for blood group determination. In the discovery cohort (N = 168), antigen A carriers (blood types A and AB) exhibited an extended progression-free survival (PFS; hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98). The association results from the SNP-derived blood were consistent with those from the measured blood group. In the validation cohort (N = 202), Cox regression analysis revealed that the antigen A carriers (rs507666 AA+GA genotype carriers) experienced significantly extended PFS compared with the non-antigen A carriers (HR = 0.61, 95% CI = 0.40-0.93). Therefore, a longer PFS was observed in antigen A carriers (P value = 0.003, HR = 0.60, 95% CI = 0.44-0.84). Furthermore, haplotype 2 carriers (rs507666 GA and rs659104 GG) demonstrated both extended PFS and improved overall survival. Notably, the presence of antigen A was not associated with the occurrence of overall immune-related adverse events (irAEs) or organ-specific toxicity. In summary, our findings revealed that antigen A carriers did not experience a higher incidence of irAEs while exhibiting better immunotherapy efficacy.

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.

Cancer remains a leading cause of mortality on a global scale. Lung cancer, specifically non-small cell lung cancer (NSCLC), is a prominent contributor to this burden. The management of NSCLC has advanced substantially in recent years, with immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), leading to improved patient outcomes. Although generally well tolerated, the administration of ICIs can result in unique side effects known as immune-related adverse events (irAEs). The occurrence of irAEs involving the lungs, specifically checkpoint inhibitor pneumonitis (CIP), can have a profound effect on both future therapy options and overall survival. Despite CIP being one of the more common serious irAEs, limited treatment options are currently available, in part due to a lack of understanding of the underlying mechanisms involved in its development. In this Review, we aim to provide an overview of the epidemiology and clinical characteristics of CIP, followed by an examination of the emerging literature on the pathobiology of this condition.

Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, has been a paradigm shift in cancer therapeutics, producing durable cancer responses across a range of primary malignancies. ICI drugs increase immune activity against tumor cells, but may also reduce immune tolerance to self-antigens, resulting in immune-mediated tissue damage. ICI-associated hepatotoxicity usually manifests as hepatocellular enzyme elevation and may occur in 2%-25% of ICI-treated patients. Although ICI-associated hepatotoxicity is clinically and pathologically distinct from idiopathic autoimmune hepatitis, our understanding of its pathogenesis continues to evolve. Pending greater understanding of the pathophysiology, mainstay of management remains through treatment with high-dose corticosteroids. This approach works for many patients, but up to 30% of patients with high-grade hepatotoxicity may not respond to corticosteroids alone. Furthermore, atypical cholestatic presentations are increasingly recognized, and rare cases of fulminant hepatitis due to ICI hepatotoxicity have been reported. Optimal management for these challenging patients remains uncertain. Herein, we review the current understanding of pathogenesis of ICI-associated toxicities, with a focus on hepatotoxicity. Based on the existing literature, we propose evolving management approaches to incorporate strategies to limit excess corticosteroid exposure, and address rare but important presentations of cholestatic hepatitis and fulminant liver failure. Finally, as ICI hepatotoxicity frequently occurs in the context of treatment for advanced malignancy, we review the impact of hepatotoxicity and its treatment on cancer outcomes, and the overall safety of re-challenge with ICI, for patients who may have limited treatment options.

The development of immune checkpoint inhibitors (ICIs) has a tremendous effect on the treatment options for multiple types of cancer. Nonetheless, there is a large interpatient variability in response, survival, and the development of immune-related adverse events (irAEs). Pharmacogenetics is the general term for germline genetic variations, which may cause the observed interindividual differences in response or toxicity to treatment. These genetic variations can either be single-nucleotide polymorphisms (SNPs) or structural variants, such as gene deletions, amplifications or rearrangements. For ICIs, pharmacogenetic variation in the human leukocyte antigen molecules has also been studied with regard to treatment outcome. This review presents a summary of the literature regarding the pharmacogenetics of ICI treatment, discusses the most important known genetic variations and offers recommendations on the application of pharmacogenetics for ICI treatment.

Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis.

We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS.

A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P = 0.028) in the homozygous model.

Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results.

To overcome the epidemiological severity of cancer, developing effective treatments is urgently required. In response, immune checkpoint inhibitors (ICIs) have been revealed as a promising resolution for treatment-resistant cancers across the world. Yet, they have both advantages and disadvantages, bringing therapeutic benefits while simultaneously inducing toxicity, and in particular, immune-mediated adverse drug reactions (imADRs), to the human body. These imADRs can be pathogenic and sometimes lethal, hampering health prediction and monitoring following the provision of ICI treatment. Therefore, it is necessary to collectively identify the determinant factors that contribute to these imADRs induced by ICIs. This article evaluated treatment-, tumor-, and patient-related determinants, and indicated a research gap for future investigations on the pathogenic mechanism of imADRs and translational conversion of determinants into clinical biomarkers to aid pharmacovigilance and cancer therapies.

Over the past few decades, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic options for the treatment of various cancers. These novel treatments effectively target key mediators of immune checkpoint pathways. Currently, ICIs primarily consist of monoclonal antibodies that specifically block cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and lymphocyte activation gene 3 protein (LAG-3). Despite the notable efficacy of ICIs in cancer treatment, they can also trigger immune-related adverse events (irAEs), which present as autoimmune-like or inflammatory conditions. IrAEs have the potential to affect multiple organ systems, with cutaneous toxicities being the most commonly observed. Although cutaneous irAEs are typically of low-grade severity and can usually be managed effectively, there are cases where severe irAEs can become life-threatening. Therefore, early recognition and a comprehensive understanding of the mechanisms underlying cutaneous irAEs are crucial for improving clinical outcomes in cancer patients. However, the precise pathogenesis of cutaneous irAEs remains unclear. This review focuses on the skin manifestations induced by ICIs, the prognosis related to cutaneous irAEs, and the exploration of potential mechanisms involved in cutaneous irAEs.

Immune checkpoint inhibitors (ICIs) have become a pillar of treatment for numerous cancers with increasing use in combination with other ICIs and in earlier stages of disease treatment. Although effective, ICI use is accompanied by a milieu of potentially bothersome or even life-threatening toxicities known as immune-related adverse events (irAEs), necessitating careful monitoring and early intervention.

In this review, we provide an overview of recent advances surrounding toxicity pathophysiology and treatment in the context of relevant organ systems. An emphasis on current treatments by toxicity, as well as updates on steroid-refractory toxicities, chronic toxicities, and biomarkers will be a focus of this update on the current understanding of irAEs.

ICI toxicities are a major limitation on the deployment of multi-agent ICI regimens and are thus a major priority to understand, treat, and prevent. Recent developments have led to greater understanding of the pathophysiology of these events, which may lead to improved prevention or mitigation strategies. Further, early studies have also suggested steroid-sparing approaches that may be useful. Ultimately, preventing and managing irAEs will be a key goal toward successful ICI treatment across a broader range of patients with cancer.

Immune checkpoints (ICs) play a central role in maintaining immune homoeostasis. The discovery that tumours use this physiological mechanism to avoid elimination by the immune system, opened up avenues for therapeutic targeting of ICs as a novel way of treating cancer. However, this therapy a new array of autoimmune side effects, termed immune-related adverse events (irAEs). In this narrative review, we first recapitulate the physiological function of ICs that are approved targets for cancer immunotherapy (CTLA-4, PD-(L)1 and LAG-3), as the groundwork to critically discuss current knowledge on irAEs. Specifically, we summarize clinical aspects and examine a molecular classification and predisposing factors of irAEs. Finally, we discuss irAE treatment, particularly emphasizing how molecular knowledge is changing the current treatment paradigm.

Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site.

PD-1/PD-L1 inhibitors have brought remarkable benefits but can cause profound immune-related adverse events (irAEs). The host immunogenetic background is likely to play a role in irAE susceptibility. In this study, we aimed to identify potential immunogenetic biomarkers to predict irAEs.

Patients with solid tumours receiving PD-1/PD-L1 blockade were recruited and followed up. Genes considered pivotal contributors to tumour-immunity and autoimmune diseases were screened out via protein-protein interaction network and Cytoscape. Consequently, thirty-nine variants in eighteen genes were genotyped using the multiplex genotyping assay. Association analysis between genetic variants and irAEs as well as irAEs-free survival was performed.

Four immunogenetic variants as predictive biomarkers of irAEs were identified. The C allele of Mitogen-Activated Protein Kinase 1 (MAPK1) rs3810610 (odds ratio [OR] = 1.495, 95% confidence interval [CI] = 1.093-2.044, P = 0.012) was a risk predictor while the A allele of PTPRC rs6428474 (OR = 0.717, 95% CI = 0.521-0.987, P = 0.041) was a protective factor for all-grade irAEs. The A allele of ADAD1 rs17388568 (OR = 2.599, 95% CI = 1.355-4.983, P = 0.003) increased the risk while the G allele of IL6 rs1800796 (OR = 0.425, 95% CI = 0.205-0.881, P = 0.018) protected patients from high-grade irAEs. Significant immunogenetic variants reached a similar tendency in PD-1 blockade or lung cancer subgroups. In multivariate Cox regression analysis, the MAPK1 rs3810610 was an independent factor regarding all-grade irAEs-free survival (CC versus CT or TT: hazard ratio [HR] = 0.71, 95% CI = 0.52-0.99, P = 0.042). ADAD1 rs17388568 (AA versus AG or GG: HR = 0.11, 95% CI = 0.025-0.49, P = 0.004) and IL6 rs1800796 (GG or GC versus CC: HR = 3.10, 95% CI = 1.315-7.29, P = 0.01) were independent variables for high-grade irAEs-free survival.

We first identified several immunogenetic polymorphisms associated with irAEs and irAEs-free survival in PD-1/PD-L1 blockade-treated tumour patients, and they may serve as potential predictive biomarkers.

Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of various cancer types. ICIs reinstate T-cell function to elicit an anti-cancer immune response. The resulting immune response can however have off-target effects which manifest as autoimmune type serious immune-related adverse events (irAE) in ~10-55% of patients treated. It is currently challenging to predict both who will experience irAEs and to what severity. Identification of patients at high risk of serious irAE would revolutionise patient care. While the pathogenesis driving irAE development is still unclear, host genetic factors are proposed to be key determinants of these events. This review presents current evidence supporting the role of the host genome in determining risk of irAE. We summarise the spectrum and timing of irAEs following treatment with ICIs and describe currently reported germline genetic variation associated with expression of immuno-modulatory factors within the cancer immunity cycle, development of autoimmune disease and irAE occurrence. We propose that germline genetic determinants of host immune function and autoimmune diseases could also explain risk of irAE development. We also endorse genome-wide association studies of patients being treated with ICIs to identify genetic variants that can be used in polygenic risk scores to predict risk of irAE.

Vitamin D (VitD) signaling has been increasingly investigated for its role in stimulating the innate and adaptive immune systems and suppressing inflammatory responses. Therefore, we examined the associations between VitD-related genetic polymorphisms, plasma 25-hydroxyvitamin D (25(OH)D), and the efficacy and safety of immune checkpoint inhibitors (ICIs).

A total of 13 single-nucleotide polymorphisms (SNPs) in VitD metabolic pathway genes were genotyped in 343 cancer patients receiving ICI treatment using the MassARRAY platform. In 65 patients, the associations between plasma 25(OH)D levels and ICI treatment outcomes were investigated further.

We found that the CYP24A1 rs6068816TT and rs2296241AA genotypes were significantly higher in patients who responded to ICIs. Furthermore, patients with higher plasma 25(OH)D levels had a better treatment response. The distribution of allele and genotype frequencies showed that three SNPs (rs10877012, rs2762934, and rs8018720) differed significantly between patients who had immune-related adverse events (irAEs) and those who did not. There was no statistically significant relationship between plasma 25(OH)D levels and the risk of irAEs.

In summary, our findings showed that genetic variations in the VitD metabolism pathway were associated with ICI treatment outcomes, and VitD supplementation may be useful in improving ICI treatment efficacy.

Immune checkpoint inhibitors (ICI) are now utilized as a standard of care treatment for multiple cancers, including in both the metastatic setting as well as in earlier stages of disease. The identification of unique immune-related adverse events (irAE) that occur during ICI treatment has led to intense research to identify potential risk factors and biomarkers that may assist in clinical decision making. Although initial studies in ICI were primarily in advanced stage disease, the use of ICI in earlier stages of disease as adjuvant therapies requires a better understanding of patient risk stratification to mitigate or prevent serious irAE.

In this review, we set out to describe the current state of research regarding potential risk factors for irAE in patients with non-small cell lung cancer, as well as explore the barriers to understanding irAE. We review data from irAE that occur in large phase 3 trials and prospective studies focusing on irAE, as well as the many retrospective studies that currently form the bulk of our understanding of irAE.

Immune-related adverse events (irAEs) are a range of complications associated with the use of immune-checkpoint inhibitors (ICIs). Two major classes of ICIs widely used are Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell death-1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors. High-grade irAEs are life-threatening and often cause a severe decline in performance status in such that patients do not qualify for any further anticancer treatments. It is difficult to generalize the evidence in the current literature on risk factors or biomarkers for the entire class of ICIs as the studies so far are either disease-specific (e.g., lung cancer or melanoma) or ICI agent-specific (e.g., pembrolizumab, ipilimumab) or irAE-specific (e.g., pneumonitis or gastritis). In this review, risk factors and biomarkers to consider before initiating or monitoring ICI are listed with a practical purpose in day-to-day practice. Risk factors are grouped into demographics and social history, medical history, and medication history, tumor-specific and agent-specific risk factors. A higher risk of irAE is associated with age <60 years, high body mass index, women on CTLA4 and men on PD-1/PD-L1 agents, and chronic smokers. Patients with significant kidney (Stage IV-V), cardiac (heart failure, coronary artery disease, myocardial infarction, hypertension), and lung (asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease) are at a higher risk of respective organ-specific irAEs. Pre-existing autoimmune disease and chronic use of certain drugs (proton pump inhibitors, diuretics, anti-inflammatory drugs) also increase the irAE-risk. Biomarkers are categorized into circulating blood counts, cytokines, autoantibodies, HLA genotypes, microRNA, gene expression profiling, and serum proteins. The blood counts and certain protein markers (albumin and thyroid-stimulating hormone) are readily accessible in current practice. High neutrophil-lymphocyte ratio, eosinophil/monocyte/lymphocyte counts; TSH and troponins at diagnosis and drop in the white count and lymphocyte count can predict irAE. Other biomarkers with limited evidence are cytokines, autoantibodies, HLA genotypes, microRNA, and gene expression profiling. With fast-expanding approvals for ICIs in various cancer types, knowledge on risk factors and biomarkers can help providers assess the irAE-risk of their patients. Prospective disease and agent-specific studies are needed to provide further insight on this essential aspect of ICI therapy.

Although PD-1/PD-L1 inhibitors are widely used as first-line treatment for patients with advanced tumors or as adjuvant therapy for patients with early-stage tumors, their efficacy is only 15-60%. Increasing evidence has demonstrated that biomarkers such as PD-L1 expression levels, microsatellite instability, and tumor mutation burden may assist in predicting the anti-tumor efficacy of PD-1/PD-L1 inhibitors. However, their clinical application value is limited, and there is currently a dearth of specific clinical markers to monitor or predict the efficacy of PD-1/PD-L1 inhibitors. Recently, studies have exposed that the efficacy of PD-1/PD-L1 inhibitors is positively correlated with immune-related adverse events (irAEs), suggesting that the latter may effectively predict anti-tumor efficacy. While there are controversies, a systematic understanding of the reasons and influencing factors of its correlation is still lacking. Therefore, this review aimed to introduce and discuss the latest research on the correlation between the efficacy of PD-1/PD-L1 inhibitors and irAEs. We identified that this positive correlation might be related to adipose tissue, T cells, pharmacokinetic characteristics, and antigen spread. In addition, the severity of irAEs, the duration of the use of PD-1/PD-L1 inhibitors, the comprehensive evaluation method of the severity of irAEs, and the genetic determinants are potentially the most significant bias factors when evaluating this correlation.

Over the past decade, the use of immune checkpoint inhibitors (ICI) has expanded across a wide spectrum of oncology indications. Immune-related adverse events (irAE) from ICIs represent a significant source of morbidity, and in rare instances, can lead to treatment-related mortality. There are significant opportunities to better identify patients at increased risk for immune-related toxicity, diagnose irAEs more accurately and earlier in their course, and develop more individualized therapeutic strategies once complications arise. Clinical characteristics, germline and somatic genetic features, microbiome composition, and circulating biomarkers have all been associated with higher risk of developing irAEs in retrospective series. Many of these data suggest that both antitumor and anti-host ICI-associated immune reactions may be driven by common features of either the tumor or the patient's preexisting immune milieu. While irAE diagnosis is currently based on clinical history, exclusion of alternative etiologies, and sometimes pathologic confirmation, novel blood-based and radiographic assays are in development to identify these complications more precisely. Anecdotal reports and small case series have highlighted the potential role of targeted immunomodulatory agents to treat irAEs, though further prospective investigation is needed to evaluate more rigorously their use in these settings. In this review, we highlight the current state of knowledge about predicting, diagnosing, and treating irAEs with a translational focus and discuss emerging strategies which aim to improve each of these domains.

Immune checkpoint blockade has revolutionized the treatment of multiple tumor types, including melanoma and nonmelanoma skin cancers. The use of immune checkpoint blockade is curtailed by tissue toxicities termed immune-related adverse events (irAEs), which occur most quickly and most often in the skin. We review the rationale for immune checkpoint blockade use, current agents, use in skin cancers, autoimmune manifestations in the skin, and considerations for predictive biomarkers and treatment options on the basis of skin pathogenesis. We also highlight major gaps in the field and the lack of preclinical modeling in the skin. A deeper understanding of irAE pathophysiology may help to uncouple toxicity and efficacy but mandates an interdisciplinary approach, including foundational skin immunology and autoimmune pathogenesis.

Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE).

In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI.

Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit.

Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.