免疫检查点抑制剂治疗黑色素瘤相关不良反应及其管理策略

近年来,免疫检查点抑制剂(ICI)在黑色素瘤治疗中取得了显著的成效,但是T细胞功能的活化也引起了一系列免疫相关不良反应(ir AE)。不同于传统化疗的不良反应,ir AE有着独特的临床表现和处理要求。虽然ir AE的发生和管理逐渐得到临床医生的重视,但一些常见ir AE的发生机制、临床表现、诊断和鉴别及其综合监测管理仍需进一步总结和归纳,以便提高临床医生工作水平和临床试验设计质量。而且不同ir AE的发生机制、糖皮质激素的治疗影响、原有自身免疫疾病患者的治疗风险等问题仍存在争议。本文阐述ICI治疗黑色素瘤引起的ir AE相关临床表现特点和诊疗管理措施,旨在对ir AE管理策略和研究方向提出具有指导意义的意见。     

肿瘤免疫检查点抑制剂治疗不良反应及其治疗——皮肤

免疫检查点抑制剂(ICPIs)已成功应用于多种恶性肿瘤的治疗,但在应用的过程中也会发生免疫相关不良反应(irAEs)。皮肤不良反应为常见的irAEs,病变较轻者主要表现为斑丘疹、苔藓样皮炎、大疱性类天疱疮、白癜风、银屑病和硬皮病;病情较重甚至危及生命的皮肤不良反应包括史提芬强生症候群和中毒性表皮坏死松解症;其他包括药疹伴嗜酸性粒细胞增多和系统症状、Sweet′s 综合征、秃头症、Grover′s病和副肿瘤综合征等。本文将对ICPIs治疗相关皮肤不良反应诊治进行综述。     

免疫检查点抑制剂常见免疫相关不良反应及其管理

目前临床上免疫检查点抑制剂(ICI)应用广泛,常见的不良反应包括皮肤、胃肠道、内分泌和肝脏不良反应,肺脏和心脏不良反应相对较少,但可能致命。类固醇全身治疗是对抗免疫治疗相关不良反应(irAE)的主要治疗手段,如对类固醇治疗没有反应,则需要考虑使用免疫调节剂。掌握irAE的发生率、发病机制、常见类型及其治疗策略,可为IC...     

免疫检查点抑制剂相关肺炎的诊治进展北大核心

过去的几年中,免疫治疗在肿瘤治疗领域取得了不可忽视的成绩,为肿瘤患者带来了新的希望,但免疫检查点抑制剂在阻断肿瘤细胞免疫逃逸的同时,也可能导致免疫耐受失衡,发生免疫相关不良反应。免疫检查点抑制剂相关肺炎是免疫检查点抑制剂应用过程中出现的免疫相关性不良反应之一,此类不良反应临床症状、影像学表现及病理表现均不典型,且有潜在的致死性,增加患者的死亡率。随着免疫检查抑制剂越来越多的投入临床,相关病例也逐渐增多,需要临床医生对高危患者密切观察,疑有免疫检查点抑制剂相关肺炎发生时及时识别、尽早做出相应的处理,并在此类肺炎痊愈后谨慎评估是否可以继续使用免疫治疗。本文就其临床表现、诊断及治疗等作一综述,以提高临床医生对此类药物治疗引起的免疫相关性肺炎的认识,为此类药物的临床应用提供参考。     

真实世界中免疫检查点抑制剂导致免疫相关不良反应病例分析

目的:探讨免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）导致的免疫相关不良反应（immune-related adverse events,irAEs）的发生情况。方法:收集并分析2018年1月至2021年3月我院irAEs的具体情况,包括基本资料、用药情况、不良反应具体情况、治疗情况等。结果:63例irAEs,包括肺毒性3例、肝脏毒性9例、皮肤毒性23例、内分泌毒性15例、神经毒性4例、肾毒性3例、胃肠毒性1例、心脏毒性2例、血液毒性1例、眼毒性2例。男性47例,女性16例,中位发病年龄61岁,不良反应中位发生时间6.6周,17例需要大剂量糖皮质激素治疗。毒性级别1-2级49例,3-4级13例,5级1例。少见irAEs 14例,1例死于心肌炎。结论:irAEs涉及的器官或系统较多,多数在3级以下。常见不良反应预后较好。少见irAEs中,心肌炎可能导致患者死亡,需要临床予以重视。     

免疫检查点抑制剂治疗相关不良反应——新探索、新挑战

近年来,通过增强机体免疫系统对肿瘤细胞的杀伤作用,免疫检查点抑制剂(immune checkpoint inhibitor,ICI)在抗肿瘤治疗中的应用获得了显著的临床疗效.然而,多项证据表明,免疫治疗在激活免疫系统的同时可导致独特的免疫相关不良反应(immune-related adverse event,irAE)...     

免疫检查点抑制剂相关内分泌不良反应的研究进展

免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）作为癌症治疗领域最重要的进展,为癌症患者带来新的希望。ICIs主要针对细胞程序性死亡受体-1（programmed cell death receptor-1,PD-1）、程序性死亡配体-1（programmed death-ligand 1,PDL1）以及细胞毒性T淋巴细胞相关蛋白-4（cytotoxic T-lymphocyte antigen-4,CTLA-4）。随着使用ICIs增加,越来越多的免疫相关不良反应（immune-related adverse effects,irAEs）被报道,其中内分泌腺体的累及尤为常见。这些irAEs的发病机制不完全明确,临床表现复杂,需要得到临床医生的充分重视。本文就ICIs作用机制及irAEs中的内分泌相关不良反应的研究进展作一综述,归纳总结其现有发病机制研究、流行病学及临床表现。      

非小细胞肺癌患者免疫检查点抑制剂相关性肺炎与免疫检查点抑制剂疗效相关性分析

目的：探讨免疫检查点抑制剂（ICI）治疗非小细胞肺癌（NSCLC）患者发生免疫检查点抑制剂相关性肺炎（CIP）的发生情况和免疫治疗疗效的关系，分析接受ICI 治疗的NSCLC患者的预后相关因素。方法：回顾性分析2020 年3月至2023 年3月在新疆医科大学附属肿瘤医院接受ICI 治疗145 例NSCLC患者的临床资料，将患者分为CIP 组和非CIP 组，随后将发生CIP 的患者分为轻度（1、2级）CIP 和重度（3、4级）CIP 两个亚组，通过Kaplan-Meier 法比较生存曲线，分析CIP 的发生及严重程度对于患者PFS 及OS的影响。通过单因素及多因素COX风险比例回归模型分析与PFS 和OS相关的预后因素。结果：145 例患者中有26例患者出现CIP，发生率为17.93％，重度CIP 发生率为3.45%。CIP 组患者PFS 明显长于非CIP 组患者（12.3 vs 7.6个月，P<0.05），CIP 组与非CIP 组的OS比较差异无统计学意义（16.2 vs 15.8个月，P>0.05)。亚组分析显示，轻度CIP 和重度CIP 相比，PFS（12.2vs 12.9 个月）及OS（16.1 vs 17.8 个月）均无统计学意义（均P>0.05）。多因素COX 回归分析显示，CIP[HR=0.55，95%CI（0.33,0.90），P=0.02]、免疫疗程>6 个[HR=0.51 ，95%CI（0.31, 0.85），P=0.01]是影响患者PFS 的有利预后因素，免疫疗程>6 个[HR=0.4，95%CI（0.18, 0.88），P=0.02]是影响OS的有利预后因素。结论：CIP 的发生率为17.93％，CIP 的发生与PFS 的延长密切相关。免疫疗程>6个是影响NSCLC患者PFS、OS的有利预后因素。     

免疫检查点抑制剂治疗肿瘤的不良反应及管理策略

免疫检查点抑制剂（immune checkpoint inhibitors,ICPIs）是现今备受关注的肿瘤治疗新方法,其拓宽了肿瘤传统治疗的边界,开启了肿瘤免疫治疗的新时代。与传统化疗药物相比,其在显著延长患者生存期（overall survival,OS）的同时减轻了免疫相关不良反应（immune-related adverse events,irAEs）。由于ICPIs全新的作用机理,且上市时间较短,其不良反应尚未有标准化的处理方案。随着免疫治疗在临床上的广泛应用,irAEs日益获得关注。本文旨在对irAEs的处理原则予以综述,为ICPIs在临床上的安全应用提供理论依据。      

免疫检查点抑制剂相关肺炎研究进展

随着癌症生物学和发病机制研究的不断深入,免疫检查点抑制剂（ICIs）得以问世,为晚期肿瘤患者带来了新的生存希望,从而开启了癌症免疫治疗的新时代,但随着免疫治疗在临床上的广泛应用,免疫相关不良事件（irAEs）也逐渐显现出来,并广泛为一线临床医师所熟知。免疫检查点抑制剂可激活T细胞攻击体内的正常组织和器官,并导致多种不良反应。而免疫检查点抑制剂相关肺炎（CIP）是irAEs中较为罕见且预后较差的并发症之一。本文参考目前国内外相关文献,就部分ICIs的治疗机制及CIP的发病率、危险因素、发生机制、临床表现、影像学表现与CIP的分级及治疗管理作一综述。     

免疫检查点抑制剂的免疫相关不良事件预测生物标志物研究进展

近年来,以免疫检查点为靶点的肿瘤免疫疗法因疗效显著而备受关注.然而随着免疫检查点抑制剂(ICIs)的推广应用,其相关不良事件(irAEs)的报道也越来越多.irAEs使接受ICIs治疗的肿瘤患者承担着额外的致命风险,限制着ICIs的使用.为帮助患者主动预防irAEs,研究具有irAEs预测价值的生物标志物意义重大.本文...     

20例晚期肿瘤患者免疫检查点抑制剂不良反应临床观察并文献复习

目的观察免疫检查点抑制剂治疗的相关不良反应。方法回顾性分析2017年3月—2019年8月在中国医学科学院肿瘤医院进行免疫检查点抑制剂治疗的20例晚期肿瘤患者临床资料,总结免疫检查点抑制剂治疗的相关不良反应。结果 20例患者免疫治疗中位时间为4.0月,发生较明确免疫治疗相关不良反应的共6例,中位时间5.3月,其中1例发生Ⅰ级免疫性胃肠炎,1例Ⅰ级免疫性皮炎,1例Ⅱ级免疫性甲状腺炎,1例Ⅲ级免疫性肝炎,1例Ⅲ级免疫性肺炎及1例Ⅳ级免疫性肺炎。结论伴随免疫治疗的相关不良反应发生率较高,严重的不良反应甚至危及生命,故免疫相关不良反应的早发现、早诊断及早干预至关重要。     

Immune-Related Adverse Events by Immune Checkpoint Inhibitors Significantly Predict Durable Efficacy Even in Responders with Advanced Non-Small Cell Lung Cancer

Background

Although predictive value of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been suggested by several studies, their assessments were insufficient because patients were categorized only by the occurrence of irAEs. It has not been elucidated whether irAEs also play a significant role even in responders.

Materials and Methods

Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICIs were enrolled in our prospective biomarker study. Twenty-three of these were responders, defined as those with complete or partial response. We investigated the proportion of irAEs among overall and responders. For responders, progression-free survival (PFS) and overall survival of ICIs were compared between those with and without irAEs. As an exploratory analysis, we measured 41 proteins from peripheral blood before and after ICI treatment.

Results

The proportion of irAEs was significantly higher in responders than nonresponders (65.2% vs. 19.3%, p < .01). Among responders, clinical characteristics did not differ regardless of the occurrence of irAEs. However, there was a significant difference in PFS among responders (irAE group 19.1 months vs. non-irAE group 5.6 months; hazard ratio: 0.30 [95% confidence interval: 0.10–0.85]; p = .02). Of 41 protein analyses, fibroblast growth factor-2 at baseline and monocyte chemoattractant protein fold change showed significant differences between them (p < .04).

Conclusion

Although this is a small sample–sized study, irAE might be a predictive factor of durable efficacy, even in patients who responded to ICIs. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI.

Implications for Practice

Although the predictive value of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) has been suggested by several studies, it has not been elucidated whether irAEs also play a significant role even in responders. This study showed that more than 60% of responders had irAEs. It demonstrated the strong correlation between irAEs and efficacy even in responders. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI.

     

Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

Background

Immune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs.

Methods

We performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate.

Results

Most patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not.

Conclusion

We found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings.

Implications for Practice

This study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.

     

Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection

BackgroundThe safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).Materials and MethodsThis was a single‐institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.ResultsWe identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1–2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).ConclusionAdverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.Implications for PracticeThe safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors’ institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.     

Cutaneous Adverse Events Associated with Immune Checkpoint Inhibitors: A Review Article

Immune checkpoint inhibitors (ICIs) have emerged as novel options that are effective in treating various cancers. They are monoclonal antibodies that target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death-ligand 1 (PD-L1). However, activation of the immune systems through ICIs may concomitantly trigger a constellation of immunologic symptoms and signs, termed immune-related adverse events (irAEs), with the skin being the most commonly involved organ. The dermatologic toxicities are observed in nearly half of the patients treated with ICIs, mainly in the form of maculopapular rash and pruritus. In the majority of cases, these cutaneous irAEs are self-limiting and manageable, and continuation of the ICIs is possible. This review provides an overview of variable ICI-mediated dermatologic reactions and describes the clinical and histopathologic presentation. Early and accurate diagnosis, recognition of severe toxicities, and appropriate management are key goals to achieve the most favorable outcomes and quality of life in cancer patients.