Biomarkers associated with immune-related adverse events induced by immune checkpoint inhibitors

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 over-view 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.

Advances on immune-related adverse events associated with immune checkpoint inhibitors

Immunotherapy has recently led to a paradigm shift in cancer therapy,in which immune checkpoint inhibitors(ICIs)are the most successful agents approved for multiple advanced malignancies.However,given the nature of the non-specific activation of effector T cells,ICIs are remarkably associated with a substantial risk of immune-related adverse events(irAEs)in almost all organs or systems.Up to 90%of patients who received ICIs combination therapy experienced irAEs,of which majority were low-grade toxicity.Cytotoxic lymphocyte antigen-4 and programmed cell death protein-1/programmed cell death ligand 1 inhibitors usually display distinct features of irAEs.In this review,the mechanisms of action of ICIs and how they may cause irAEs are described.Some unsolved challenges,however really engrossing issues,such as the association between irAEs and cancer treatment response,tumor response to irAEs therapy,and ICIs in challenging populations,are comprehensively summarized.

Immune-related adverse events induced by programmed death protein-1 inhibitors from the perspective of lymphoma immunotherapy

Lymphoma,which is highly malignant,stems from lymph nodes and lymphoid tissue.Lymphoma cells express programmed death-ligand 1/2(PD-L1/PD-L2),which binds with programmed cell death 1 protein(PD-1)to establish inhibitory signaling that impedes the normal function of T cells and allows tumor cells to escape immune system surveillance.Recently,immune checkpoint inhibitor immunotherapies such as PD-1 inhibitors(nivolumab and pembrolizumab)have been introduced into the lymphoma treatment algorithm and have shown remarkable clinical efficacy and greatly improve prognosis in lymphoma patients.Accordingly,the number of lymphoma patients who are seeking treatment with PD-1 inhibitors is growing annually,which results in an increasing number of patients developing immune-related adverse events(irAEs).The occurrence of irAEs inevitably affects the benefits provided by immunotherapy,particularly when PD-1 inhibitors are applied.However,the mechanisms and characteristics of irAEs induced by PD-1 inhibitors in lymphoma need further investigation.This review article summarizes the latest research advances in irAEs during treatment of lymphoma with PD-1 inhibitors.A comprehensive understanding of irAEs incurred in immunotherapy can help to achieve better efficacy with PD-1 inhibitors in lymphoma.

Immune checkpoint inhibitor-associated gastritis:Patterns and management

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

Managing immune checkpoint inhibitor-associated gastritis: Insights and strategies

Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the discontinuation of ICIs.

Gastric microbiota transplantation as a potential treatment for immune checkpoint inhibitor-associated gastritis

Immune-related adverse events(irAEs)are complications of the use of immune checkpoint inhibitors(ICIs).ICI-associated gastritis is one of the main irAEs.The gastric microbiota is often related to the occurrence and development of many gastric diseases.Gastric microbiota adjustment may be used to treat gastric disorders in the future.Faecal microbiota transplantation can alter the gut microbiota of patients and has been used for treating ICI-associated colitis.Therefore,we propose gastric microbiota transplantation as a supplementary treatment for patients with ICI-associated gastritis who do not respond well to conventional therapy.

Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma:A retrospective study

BACKGROUND Although immune checkpoint inhibitor(ICI)therapy has improved the prognosis of unresectable hepatocellular carcinoma(HCC),it has also resulted in unique immune-related adverse events(irAEs).The relationship between irAE and treatment outcomes in ICI-treated unresectable HCC patients remains unknown.AIM To elucidate the correlation between immune-related toxic effects and prognosis in patients with unresectable HCC treated with pembrolizumab.METHODS From March 2019 to February 2021,a total of 190 unresectable HCC(Barcelona Clinic Liver Cancer C)patients receiving pembrolizumab treatment were retrospectively reviewed.Overall survival(OS)was the primary endpoint,while objective response rate(ORR),disease control rate(DCR),and time to progression(TTP)were secondary evaluation indexes.We assessed demographics,irAEs,and outcomes by retrospective review.RESULTS One hundred and forty-three males and 47 females were included in the study.The ORR and DCR were 12.1%(23/190)and 52.1%(99/190),respectively.The median OS was 376 d[95%confidence interval(CI):340-411 d]and the median TTP was 98 d(95%CI:75-124 d).The overall incidence of treatment-related adverse events was 72.6%(138/190)and 10.0%of them were severe irAEs(grade≥3).Child-Pugh B class,portal vein tumor thrombus,extrahepatic metastasis,and hypothyroidism were the independent risk factors for survival.Patients with hypothyroidism showed a longer OS[517 d(95%CI:423-562)vs 431 d(95%CI:412-485),P=0.011]and TTP[125 d(95%CI:89-154)vs 87 d(95%CI:61-98),P=0.004]than those without irAEs.CONCLUSION Pembrolizumab-treated patients with unresectable HCC who experienced hypothyroidism have promising ORR and durable response.Hypothyroidism,an irAE,may be used as a clinical evaluation parameter of response to ICIs in unresectable HCC.

Immune checkpoint inhibitor-associated ophthalmic adverse events: current understanding of its mechanisms,diagnosis, and management

Immune checkpoint inhibitors(ICIs) targeting cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 receptor/ligand have revolutionized cancer treatment, achieving unprecedented efficacy in numerous malignancies. Despite the excellent therapeutic effects of ICIs, medications, such as pembrolizumab, ipilimumab, nivolumab, atezolizumab, avelumab, and durvalumab, typically cause a broad spectrum of toxicity events termed as immune-related adverse events(ir AEs). Out of all ir AEs, ophthalmic adverse events occur infrequently and are not comprehensively recognized. The current understanding of ophthalmic ir AEs is mainly derived from case reports and case series. In this review, based on relevant articles in the literature and current evidence, we summarize the incidences, manifestations, diagnoses, underlying mechanisms, treatments, and outcomes of ophthalmic ir AEs and discuss possible management strategies. A better understanding of these features is critical for managing patients with ICI-associated ophthalmic adverse events.

Application of immune checkpoint inhibitors and microsatellite instability in gastric cancer

In this editorial we comment on the article by Li published in the recent issue of the World Journal of Gastroenterology.We focus specifically on the application of immune checkpoint inhibitors(ICIs)and microsatellite instability(MSI)in gastric cancer(GC).The four pillars of GC management have long been considered,including surgery,chemotherapy,radiotherapy and targeted therapy.However,immunotherapy has recently emerged as a“fifth pillar”,and its use is rapidly expanding.There are four principal strategies for tumor immunotherapy:ICIs,tumor vaccines,adoptive immunotherapy and nonspecific immunomodulators.Of them,ICIs are the most advanced and widespread type of cancer immunotherapy for GC.Recent breakthrough results for ICIs have paved the way to a new era of cancer immunotherapy.In particular,inhibition of the PD-1/PD-L1 axis with ICIs,including nivolumab and pembrolizumab,has emerged as a novel treatment strategy for advanced GC.Unfortunately,these therapies are sometimes associated with often subtle,potentially fatal immune-related adverse events(irAEs),including dermatitis,diarrhea,colitis,endocrinopathy,hepatotoxicity,neuropathy and pneumonitis.We must be aware of these irAEs and improve the detection of these processes to prevent inappropriate discharges,emergency department revisits,and downstream complications.Recent studies have revealed that MSI-high or mismatch-repair-deficient tumors,regardless of their primary site,have a promising response to ICIs.So,it is important to detect MSI before applying ICIs for treatment of GC.

Cytokine release syndrome induced by anti-programmed death-1 treatment in a psoriasis patient:A dark side of immune checkpoint inhibitors

In recent years,cancer immunotherapy has introduced novel treatments,such as monoclonal antibodies,which have facilitated targeted therapies against tumor cells.Programmed death-1(PD-1)is an immune checkpoint expressed in T cells that regulates the immune system’s activity to prevent over-activation and tissue damage caused by inflammation.However,PD-1 is also expressed in tumor cells and functions as an immune evasion mechanism,making it a therapeutic target to enhance the immune response and eliminate tumor cells.Consequently,immune checkpoint inhibitors(ICIs)have emerged as an option for certain tumor types.Nevertheless,blocking immune checkpoints can lead to immune-related adverse events(irAEs),such as psoriasis and cytokine release syndrome(CRS),as exemp-lified in the clinical case presented by Zhou et al involving a patient with adva-nced gastric cancer who received sintilimab,a monoclonal antibody targeting PD-1.Subsequently,the patient experienced exacerbation of psoriasis and CRS.The objective of this editorial article is to elucidate potential immunologic mechanisms that may contribute to the development of CRS and psoriasis in patients receiving ICIs.It is crucial to acknowledge that while ICIs offer superior safety and efficacy compared to conventional therapies,they can also manifest irAEs affecting the skin,gastrointestinal tract,or respiratory system.In severe cases,these irAEs can lead to life-threatening complications such as circulatory shock or multiorgan failure.Consequently,it is recommended that patients receiving ICIs undergo regular monitoring to identify and manage these adverse events effectively.

Cardiac adverse events of immune checkpoint inhibitors in oncology patients:A systematic review and meta-analysis

BACKGROUND Immune checkpoint inhibitors(ICIs)are novel therapeutic agents used for various types of cancer.ICIs have revolutionized cancer treatment and improved clinical outcomes among cancer patients.However,immune-related adverse effects of ICI therapy are common.Cardiovascular immune-related adverse events(irAEs)are rare but potentially life-threatening complications.AIM To estimate the incidence of cardiovascular irAEs among patients undergoing ICI therapy for various malignancies.METHODS We conducted this systematic review and meta-analysis by searching PubMed,Cochrane CENTRAL,Web of Science,and SCOPUS databases for relevant interventional trials reporting cardiovascular irAEs.We performed a single-arm meta-analysis using OpenMeta[Analyst]software of the following outcomes:Myocarditis,pericardial effusion,heart failure,cardiomyopathy,atrial fibrillation,myocardial infarction,and cardiac arrest.We assessed the heterogeneity using the I2 test and managed to solve it with Cochrane’s leave-one-out method.The risk of bias was performed with the Cochrane’s risk of bias tool.RESULTS A total of 26 studies were included.The incidence of irAEs follows:Myocarditis:0.5%[95%confidence interval(CI):0.1%-0.9%];Pericardial effusion:0.5%(95%CI:0.1%-1.0%);Heart failure:0.3%(95%CI:0.0%-0.5%);Cardiomyopathy:0.3%(95%CI:-0.1%-0.6%);atrial fibrillation:4.6%(95%CI:1.0%-14.1%);Myocardial infarction:0.4%(95%CI:0.0%-0.7%);and Cardiac arrest:0.4%(95%CI:0.1%-0.8%).CONCLUSION The most common cardiovascular irAEs were atrial fibrillation,myocarditis,and pericardial effusion.Although rare,data from post market surveillance will provide estimates of the long-term prevalence and prognosis in patients with ICIassociated cardiovascular complications.

Treatment-related adverse events of combined anti-angiogenic and immune checkpoint inhibitors:systematic review and meta-analysis

Objective Immune checkpoint inhibitor(ICI)plus angiogenesis inhibitor(AI)combination therapy is a novel treatment model for multiple cancers that normalizes vascular-immune crosstalk to potentiate cancer immunity.In this review,we summarize the characteristics of adverse effects(AEs)and all fatal cases reported in clinical studies involing ICI+AI therapy.Methods Four databases were systematically searched for eligible studies,and 28 relevant studies were selected for inclusion.Results Of the patients included,58.1%developed grade≥3 AEs.The most common fatal AEs were cardiovascular events,severe infections,and hemorrhage.Compared with AI alone,ICI+AI therapy resulted in more cases of grade≥3 proteinuria,liver injury,and fatal AEs(2.49%vs.1.28%,P=0.0041),especially respiratory toxicities and severe infections;however,ICI+AI therapy reduced hematological toxicity.Conclusion We shared comprehensive and practical safety data to review the adverse events associated with ICI+AI treatment.

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events

Objective:We aimed to retrospectively analyze the toxicity profiles and predictors of immune-related adverse events(irAEs)as well as the correlation between irAEs and the clinical efficacy of multi-type immune checkpoint inhibitors(ICIs)in patients with advanced pan-cancer in a real-world setting.Methods:We retrospectively analyzed data from 105 patients with advanced pan-cancer treated with multi-type ICIs at the First Hospital of Jilin University between January 1,2016 and August 1,2020.We used logistic regression analyses to investigate the associations of irAEs with clinical baseline characteristics,blood count parameters,and biochemical indicators during treatment.Receiver operating characteristic curves were used to determine cutoff values for parameters and area under the curve values.Kaplan–Meier and Cox multivariate regression analyses were performed to estimate the relationships of baseline characteristics and irAEs with progression-free survival(PFS)and overall survival(OS).Results:A lower relative lymphocyte count(cutoff=28.5%),higher albumin level(cutoff=39.05 g/L),and higher absolute eosinophil count(AEC)(cutoff=0.175×10^(9)/L)were significantly associated with the occurrence of irAEs,among which a higher AEC(cutoff=0.205×10^(9)/L)was strongly associated with skin-related irAEs[odds ratios(ORs)=0.163,P=0.004].Moreover,a higher lactate dehydrogenase level(cutoff=237.5 U/L)was an independent predictor of irAEs of grade≥3(OR=0.083,P=0.023).In immune cell subgroup analysis,a lower absolute count of CD8+CD28−suppressor T cells(OR=0.806;95%confidence interval:0.643–1.011;P=0.062),which are regulatory T lymphocytes,was associated with the occurrence of irAEs,although the difference was not statistically significant.Furthermore,a higher percentage of CD19+B cells was associated with the occurrence of irAEs of grade≥3(P=0.02)and grade≥2(P=0.051).In addition,patients with any grade of irAE had a significantly high PFS(8.37 vs.3.77 months,hazard ratios(HR)=2.02,P=0.0038)and OS(24.77 vs.13.83 months,HR=1.84;P=0.024).Conclusions:This retrospective study reports clinical profile data for irAEs in unselected patients in a real-world setting and explored some parameters that may be potential predictive markers of the occurrence,type,or grade of irAEs in clinical practice.Evidence of a correlation between safety and efficacy may facilitate a complete assessment of the risk-benefit ratio for patients treated with ICIs.

Use of traditional Chinese medicine in the treatment of immune-related adverse events of cancer immunotherapy

Immune checkpoint inhibitors(ICPI)have shown considerable promise in the treatment of tumors.However,immune-related adverse events(irAEs)caused by ICPI have been reported in nearly every organ system.Whilst this represents a new challenge in the field of cancer treatment,traditional Chinese medicine(TCM)provides benefits in the treatment of irAEs.This article reviews the studies of the treatment of immune-related gastrointestinal diseases and dermatosis with TCM and introduces the collaborative efforts between China and France in the implementation of TCM for the treatment of irAEs.

Management and nursing strategies for different patterns of adverse events in patients with urological cancer treated with immune checkpoint inhibitors

Background This study aimed to explore the patterns of treatment-related adverse events(AEs)associated with immune checkpoint inhibitor(ICI)monotherapy and in combination with chemotherapy or tyrosine kinase inhibitor(TKI)therapy and to summarize the corresponding management and nursing strategies.Materials and methods A total of 69 patients with malignant urological tumors who received ICI treatment between June 2019 and October 2022 were retrospectively analyzed,and AEs that occurred during treatment were observed and reported.Based on the different types of treatment,the patients were divided into ICI monotherapy,ICI plus chemotherapy,and ICI plus TKI therapy groups.Subgroup analysis was performed.The incidence,distribution,and severity of AEs in the different subgroups were evaluated.Results A total of 138 AEs occurred in 69 patients,among which grade 1 plus 2,and grade 3 plus 4 AEs accounted for 78.99%and 21.01%,respectively.The incidence of AEs per patient in the ICI-TKI therapy group was the highest(3.75 times/person),followed by the ICI-chemotherapy(2.33 times/person)and ICI monotherapy(0.82 times/person)groups.Specific AEs,such as fatigue,nausea,and myelosuppression,were much more common in the ICI-gemcitabine and cisplatin group,whereas renal injury,skin lesions,and diarrhea were most common ones in the ICI-TKI group.Conclusions Immune checkpoint inhibitors are new treatment options for advanced urological tumors and renal cell carcinoma.Distinctive AE patterns were observed among the different treatment groups.Therefore,strict and meticulous clinical management and nursing measures are required to ensure the safety of patients receiving ICI treatment.

Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival

BACKGROUND Immune checkpoint inhibitor-mediated colitis(IMC)is a common adverse event following immune checkpoint inhibitor(ICI)therapy for cancer.IMC has been associated with improved overall survival(OS)and progression-free survival(PFS),but data are limited to a single site and predominantly for melanoma patients.AIM To determine the association of IMC with OS and PFS and identify clinical predictors of IMC.METHODS We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age,sex,ICI class,and malignancy to a cohort of ICI users without IMC,from May 2011 to May 2020.Using univariate and multivariate logistic regression,we determined association of presence of IMC on OS,PFS,and clinical predictors of IMC.Kaplan-Meier curves were gen-erated to compare OS and PFS between ICI users with and without IMC.RESULTS IMC was significantly associated with a higher OS(mean 24.3 mo vs 17.7 mo,P=0.05)but not PFS(mean 13.7 mo vs 11.9 mo,P=0.524).IMC was significantly associated with OS greater than 12 mo[Odds ratio(OR)2.81,95%confidence interval(CI)1.17-6.77].Vitamin D supplementation was significantly associated with increased risk of IMC(OR 2.48,95%CI 1.01-6.07).CONCLUSION IMC was significantly associated with OS greater than 12 mo.In contrast to prior work,we found that vitamin D use may be a risk factor for IMC.

Immune Checkpoint Inhibitor Related Neuropathic Adverse Effects on Cancer Patients

With the recent development and clinical application, immune checkpoint inhibitors (ICIs) intervention is being increasingly common for multiple malignancies. With these, prospect on focus creates an increasing necessity for an early recognition with proper documentation of upcoming treatment-related toxicities. These treatment-related toxicities are generally termed as immune-related adverse effects (irAEs) [1]. It is a known fact that the upregulation of T-cell initiates autoimmunity resulting in these irAEs. The review focuses on increasing events of neuropathy associated with immunecheckpoint inhibitors, which is one of the rare neurological irAEs, therefore, the least reviewed. The severity and distribution of neurologic toxicities are important deciding factors for its management (CNS vs. PNS), although there is no strong evidence for patients treated with ICIs are specifically affected by the use of immune-modulating interventions. Furthermore, the review discusses on pathophysiology, incidence, clinical presentation, diagnosis, and management of neuropathies as a result of ICIs. Early administration of high-dose corticosteroids is the main management of neuropathies especially for grade 3 or 4 irAEs initial cessation of ICI therapy with continued steroids which are necessary. However, the optimal duration of ICI therapy to minimize the risk of toxicity should be kept under consideration.

Comment on “Disease exacerbation is common in inflammatory bowel disease patients treated with immune checkpoint inhibitors for malignancy”

We recently read with interest the original research article entitled"Disease exacerbation is common in inflammatory bowel disease patients treated with immune checkpoint inhibitors for malignancy".The abovementioned article is an observational retrospective cohort study,which could be of particular value for clinicians to understand how immunotherapy affects pre-existing enteral disease in inflammatory bowel disease patients.Although we appreciate the endeavor of Samuel Rubin et al,based on our in-depth analysis,we detected a potential shortcoming in this article;thus,we present our comments in this letter.If the authors contemplate these comments on their relevant research,we believe that their contribution would be considerable for future studies.

Immune checkpoint inhibitor-induced colitis:A comprehensive review

Immune checkpoint inhibitors(ICIs) are monoclonal antibodies that target downregulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1.ICIs have revolutionized the treatment of a variety of malignancies. However,many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis(IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease,however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.

Immune checkpoint inhibitor-related hepatotoxicity:A review

The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,disease stages and lines of therapy.With this increased use,adverse events including immune checkpoint inhibitor-related hepatotoxicity(ICH)have emerged as an important clinical problem.This along with the introduction of ICI as first-and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists.The incidence of ICH varies between 1%-20%depending on the number,type and dose of ICI received.Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI,corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity.The majority of patients with ICH recover and some may even safely recommence ICI therapy.Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.