Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio:Markers predicting immune-checkpoint inhibitor efficacy and immune-related adverse events

We conducted a comprehensive review of existing prediction models pertaining to the efficacy of immune-checkpoint inhibitor(ICI)and the occurrence of immune-related adverse events(irAEs).The predictive potential of neutrophil-to-lymphocyte ratio(NLR)and platelet-to-lymphocyte ratio(PLR)in determining ICI effectiveness has been extensively investigated,while limited research has been conducted on predicting irAEs.Furthermore,the combined model incor-porating NLR and PLR,either with each other or in conjunction with additional markers such as carcinoembryonic antigen,exhibits superior predictive capabilities compared to individual markers alone.NLR and PLR are promising markers for clinical applications.Forthcoming models ought to incorporate established efficacious models and newly identified ones,thereby constituting a multifactor composite model.Furthermore,efforts should be made to explore effective clinical application approaches that enhance the predictive accuracy and efficiency.

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-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.

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.

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.

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.

Delayed immune-related sclerosing cholangitis after discontinuation of pembrolizumab:A case report

BACKGROUND Secondary sclerosing cholangitis,characterized by biliary obstruction,can be caused by drugs such as immune checkpoint inhibitors(ICIs).While there a few reports of sclerosing cholangitis after immune checkpoint inhibitor administration,no case has been reported after discontinuation of such drugs.CASE SUMMARY A 68-year-old man who underwent chemotherapy for lung adenocarcinoma with bone metastasis presented with abdominal pain and fever 4 mo after the final administration of pembrolizumab.Computed tomography revealed thickening of the gallbladder wall and dilatation of the common bile duct.Endoscopic retrograde cholangiopancreatography revealed an irregularly narrowed intrahepatic bile duct.Biopsy of the bile duct demonstrated that CD8+T cells were predominant over CD4+T cells.Liver biopsy showed dominant infiltration of CD8+T in the portal tract,but onion-skin lesions were not observed.The patient was diagnosed with immune-related sclerosing cholangitis induced by pembrolizumab.Administration of methylprednisolone and endoscopic nasobiliary drainage were performed,but the cholangiography and laboratory test findings did not improve.No further treatment was administered due to disease progression,and the patient was referred for palliative care.CONCLUSION Immune-related sclerosing cholangitis may have a late onset,and such cases occurring after discontinuation of ICIs should be carefully managed.

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.

Pathogenesis,pathological characteristics and individualized therapy for immune-related adverse effects

Immune checkpoint inhibitors(ICIs)are a class of antitumor medications that target immune checkpoints,which induce the activation of lymphocytes.These treatments effectively prolong the survival of patients with advanced tumors,especially lung cancer.However,in addition to tumor killing effects,ICIs may also cause an imbalance between immune tolerance and immunity.Over-activated lymphocytes may cause various types of damage to multiple organs throughout the body,called immune-related adverse events.In this review,we summarize the pathogenesis,pathological characteristics,biomarkers,and therapeutic agents for immune-related adverse events.

免疫检查点抑制剂相关皮肤不良反应管理的证据总结

目的 检索、评价并整合免疫检查点抑制剂(ICIs)相关皮肤不良反应(irAEs)管理的相关证据。方法 系统检索循证决策支持系统BMJ Best Practice、JBI图书馆、Cochrane图书馆、英国国家卫生和临床优化研究所、苏格兰校际指南、Web of science、美国国立综合癌症网络等专业学会网站、PubMed、中国生物医学文献数据库、中国知网、万方中关于ICIs irAEs管理的指南、证据总结、专家共识、系统评价,检索时间限定为2013年1月1月-2022年10月31日。对检索的文献进行质量评价后,再对证据进行提取和整合。结果 共纳入9篇文献,其中包括4篇指南、1篇证据总结、4篇专家共识。经过阅读、提取和归纳,共总结出14条证据,包括培训、健康教育、评估与监测和治疗4个方面。结论 临床医护人员应应用最佳证据对ICIs irAEs进行规范管理,降低irAEs的发生。

关注免疫检查点抑制剂发生irAE后免疫治疗再挑战

免疫检查点抑制剂(immune-checkpoint inhibitors,ICIs)是近年来肿瘤学领域最重要的突破之一,为不同类型的实体瘤治疗提供了新的范式。ICIs通过阻断免疫内在下调因子,如细胞毒性T淋巴细胞抗原4(CTLA-4)和程序性细胞死亡1(PD-1)或其配体程序性细胞死亡配体1(PD-L1),增加抗肿瘤免疫力[1]。然而,由于免疫应答增强和免疫系统失衡,患者可能会发生免疫相关不良事件(immune-related adverse events,irAE)。

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.

102例临床应用卡瑞利珠单抗的安全性分析

目的:探究卡瑞利珠单抗治疗恶性肿瘤患者的用药安全性,为临床安全合理用药提供参考。方法:回顾性分析2021年3月4日~2023年10月30日期间于某院使用注射用卡瑞利珠单抗治疗的102例肿瘤患者,统计其基本资料、用药信息、联合用药情况、免疫相关不良事件(irAEs)发生情况、处理措施与转归等。结果:患者年龄32~86岁;男性66例,女性36例;男女比例为11∶6;60例(58.82%)合并基础疾病,52例(50.98%)联合使用抗血管生成药物(如仑伐替尼、安罗替尼、阿帕替尼)。共49例患者发生irAEs,其中以反应性毛细血管增生症(RCCEP)最为常见,大多为G1~G2级。卡瑞利珠单抗联合抗血管生成药物可显著降低irAEs的发生率(P<0.05)。卡瑞利珠单抗治疗合并基础疾病患者的irAEs发生率高于无基础疾病的患者(P<0.05)。结论:临床应用卡瑞利珠单抗时,irAEs发生率较高,但严重程度均较轻,大多为G1~G2级,且多数在治疗后可缓解。

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.

Untoward immune effects of modern medication

Immune-related adverse events(irAEs)represent an increasingly concerning challenge in the assessment of biopharmaceutical products.In contrast to historically rare allergic reactions associated with small chemical drugs,contemporary biotherapeutics exhibit a significantly higher morbidity of irAEs,because of their complex structure and comprehensive mechanisms of action.While the immunogenicity of protein-based compounds is associated with the induction of anti-drug antibodies,the pathogenesis of irAEs in advanced biologics,such as cell and gene therapy,remains to be further delineated.In the current study,I present an updated profile regarding the untoward immune effects of medications,covering various material categories systematically,with the underlying mechanisms to inspire risk mitigation in biopharmaceutical development and application.

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.

癌症患者免疫相关皮肤不良反应预防及管理的证据总结

目的:系统检索、评价并提取总结国内外关于癌症患者免疫相关皮肤不良反应预防及管理的相关证据。方法:依据“6S”金字塔模型,自上而下系统检索相关网站和数据库中关于癌症患者免疫相关皮肤不良反应预防及管理的文献,检索时限为2013年1月1日至2023年12月31日。对纳入的文献进行质量评价后提取证据并整合。结果:共纳入16篇文献,其中指南7篇、临床决策1篇、专家共识6篇、系统评价2篇,从多学科团队、基线评估、皮肤日常管理、早期诊断、症状处理、随访监测、健康教育7个方面形成了28条证据。结论:本研究总结了癌症患者免疫相关皮肤不良反应预防及管理的相关证据,可以为临床医护人员制定皮肤不良反应管理策略提供参考,但对患者开展临床实践时仍需要结合临床实际情况和患者个体需求选择适宜的证据。

临床药师参与1例纳武利尤单抗致棘皮瘤的处置与分析

本文报道了临床药师参与的1例纳武利尤单抗致棘皮瘤患者的诊治过程。该例患者使用纳武利尤单抗2周后发生棘皮瘤,累及头皮、颈部、躯干、手背、脚底等部位,并伴有中度瘙痒,经临床药师按照不良反应因果关系评价方法判定为“肯定”。临床药师查阅文献发现,免疫检查点抑制剂致棘皮瘤以男性、高龄、恶性黑色素瘤患者多见,好发于躯干、四肢及手部,局部手术及糖皮质激素治疗是主要的处置手段。临床药师在考虑治疗药物有效性、安全性、经济性、可及性的基础上,最大限度尊重患者意愿,与医师讨论后决定予患者卤米松乳膏外用+维A酸胶囊口服+依巴斯汀片口服的综合治疗方案,并予患者继续使用纳武利尤单抗行免疫治疗,同时由临床药师进行药学监护和心理疏导。最终,该例患者顺利完成治疗,棘皮瘤在纳武利尤单抗治疗结束后逐渐消退。该例患者的诊治过程表明,临床药师的参与有助于提高患者免疫治疗的连续性与安全性。

度伐利尤单抗致反应性皮肤毛细血管增生症1例

目的 分析度伐利尤单抗致反应性皮肤毛细血管增生症(RCCEP)1例,提示临床需重视度伐利尤单抗引起的新型免疫相关不良反应。方法 分析1例晚期肺癌患者使用度伐利尤单抗期间出现RCCEP的病例,并结合文献阐述度伐利尤单抗引起RCCEP的可能原因。结果 本例患者出现RCCEP可能是度伐利尤单抗所致。服用阿帕替尼后,患者RCCEP症状得到缓解。结论 加强度伐利尤单抗使用期间的用药监护及用药教育,定期观察患者的皮肤情况,及时准确地获取患者相关症状,并施以针对性治疗方案,可有效避免患者不良反应症状加重。

程序性细胞死亡蛋白-1(PD-1)抑制剂致皮肤免疫相关不良反应的临床观察

目的探讨程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)抑制剂临床应用中的皮肤免疫相关不良反应(immune-related adverse events,irAEs)的发生和结局。方法回顾性队列研究2020年3月至2022年11月接受PD-1抑制剂治疗恶性肿瘤的患者456例,观察出现皮肤irAEs的种类、分级及治疗和预后。结果接受PD-1抑制剂治疗的患者中共有101例患者发生irAEs,其中反应性毛细血管增生症(reactive cutaneous capillary endothelial proliferation,RCCEP)71例(占比70.29%),其中2级15例,1级56例,大多数患者未予特殊治疗,少部分患者加用阿帕替尼抗血管治疗后血管瘤消退;皮肤瘙痒22例(占比21.7%),其中2级4例,1级18例,外用糖皮质激素和口服抗组胺药治疗,症状在1周内好转;斑丘疹15例(占比14.8%),其中1级皮肤不良反应9例,2级皮肤不良反应6例,使用润肤剂、外用糖皮质激素和口服抗组胺药进行对症治疗后好转;白癜风样色素脱失4例(占比3.9%),其中2级1例,1级3例,均未进行特殊治疗;中毒性表皮坏死松解症(toxic epidermal necrolysis,TEN)1例,ICU支持治疗及激素抗生素应用后,皮损好转;银屑病样反应1例,为3级皮肤反应,静脉使用糖皮质激素药物后,皮损好转。结论PD-1发生的irAEs中,分级主要为1~3级,4级以上罕见。irAEs对症处理后,绝大多数可以缓解。皮肤irAEs的早期识别和充分管理可以预防症状发展恶化,皮肤irAEs总体安全可控。