免疫治疗导致的心脏毒性相关研究进展

免疫治疗在多种实体肿瘤和血液系统恶性肿瘤的治疗中均表现出了显著的疗效,其应用日益广泛。然而,随着临床实践的不断深入,发现免疫检查点抑制剂（immune checkpoint inbibitors,ICIs）在激活免疫系统的同时,还会引起广泛的不良反应,称为免疫相关不良事件（immune related adverse events,irAEs）。免疫检查点抑制剂治疗可诱导多种严重的irAEs,其中,心脏毒性与高死亡率相关[1],但其潜在的病理机制尚不明确。ICIs相关心脏毒性有多种表现形式,包括心肌炎、心包炎、心律失常、传导障碍和心室功能损害等。虽然这些毒性几乎可以影响任何器官,但最致命的是心肌炎。本文阐述了ICIs相关心脏毒性的作用机制及ICIs基础研究模型的种类和特点。此外,我们还对心肌、心包、心血管系统和传导系统的免疫相关不良事件的发病时间、症状、诊断和治疗进行了探讨。     

肿瘤免疫治疗相关性垂体炎诊治现状及研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)作为一种新型的癌症治疗方法,使癌症治疗模式发生了重大变化。ICIs是一种单克隆抗体,能抑制免疫反应的负调节成分,从而刺激T细胞对抗癌细胞。ICIs主要包括三类:细胞毒性T淋巴细胞相关抗原4(cytotoxic T⁃lymphocyte⁃associated protein 4,CTLA⁃4)抑制剂、程序性细胞死亡受体1(programmed cell death 1,PD⁃1)及其配体(PD⁃L1/PD⁃L2)抑制剂。尽管ICIs在临床上取得了成功,但也带来了挑战,其中包括免疫相关不良事件。ICIs引起的最常见不良事件之一是内分泌疾病,而免疫性垂体炎是癌症患者常见的免疫相关不良事件。本文就ICIs治疗相关性垂体炎(immune⁃related hypophysitis,irH)的诊断标准、临床表现及特点、可能的分子机制及其预测标志物作一综述。     

免疫检查点抑制剂相关的毒性多学科诊疗协作组建设中国专家共识

以程序性细胞死亡蛋白-1/程序性细胞死亡配体-1(PD-1/PD-L1)抑制剂和细胞毒性T淋巴细胞相关抗原4(CTLA-4)抑制剂为代表的免疫检查点抑制剂(ICIs)作为新型免疫治疗手段,已经给恶性肿瘤患者带来了显著的临床获益,延长患者生存。自2011年以来,国内外已经有10余款ICIs陆续获批上市,接近一半的实体瘤患者有ICIs治疗的适应证。然而,ICIs相关的毒性,或称为免疫相关不良反应(irAEs)随之而来,不仅极大地影响了临床治疗决策,而且在一定程度上也限制了ICIs的临床应用和患者持续获益。为优化irAEs管理,完善irAEs多学科诊疗协作组(MDT)建设的标准化、流程化,提高MDT讨论的质量和效率,为患者提供高效、优化的诊疗方案,减轻患者痛苦,提高生活质量,继而改善患者预后,并推动跨学科MDT的规范化发展,中国临床肿瘤学会(CSCO)免疫治疗专家委员会、CSCO抗肿瘤药物安全管理专家委员会组织领域内多名专家,参考国内外癌症中心对irAEs的MDT管理经验及有关重要文献,认真讨论,多次修改,形成了本专家共识,作为各肿瘤中心irAEs MDT运行和操作的重要参考。     

免疫检查点抑制剂特殊人群应用专家共识

免疫检查点抑制剂(ICIs)作为新型免疫治疗手段,已使许多恶性肿瘤患者的预后得到了显著改善。自2018年以来,国家药品监督管理局已陆续批准了10余种ICIs治疗晚期实体瘤适应证。随着ICIs逐渐成为一种广谱的抗肿瘤手段,治疗人群在不断扩展。其中,特殊人群,即具有某些临床病理特征的肿瘤患者,既往常被排除在ICIs临床试验之外。即便《中国临床肿瘤学会(CSCO)免疫检查点抑制剂相关的毒性管理指南》对特殊人群使用ICIs前进行筛查做了初步推荐,但全程管理建议仍然不足。为了更好地指导特殊人群合理、安全使用ICIs,CSCO免疫治疗专家委员会组织多学科专家,经充分酝酿和讨论,最终形成本共识,作为临床医师用药时的重要参考。     

卡瑞利珠单抗联合化疗治疗局部晚期食管癌引起心源性休克一例

<正>食管癌在全球癌症发病率中排第7位,在癌症相关死亡原因中排第6位^[1]。病理类型上,食管癌主要为食管鳞癌(esophageal squamous cell carcinoma,ESCC)和食管腺癌。ESCC占>90%,中国约60%～70%的患者确诊时为局部晚期或晚期,治疗手段局限且效果不佳^[2]。免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)改变了ESCC的治疗格局,但免疫相关不良反应(immunerelated adverse events,irAEs)也随之出现,其中心脏毒性尤其是免疫性心肌炎罕见但致命。本文报道1例新辅助应用卡瑞利珠单抗联合化疗治疗的局部晚期ESCC病例,治疗效果良好且手术成功,但术后经历4级ICIs相关应激性心肌炎合并心源性休克,为ESCC术前联合治疗模式及免疫性心肌炎的诊治提供经验和参考。     

免疫检查点抑制剂治疗相关静脉血栓栓塞症的研究进展

近年来,静脉血栓栓塞症(venous thromboembolism, VTE)已成为仅次于恶性肿瘤本身的第二位死亡原因。在精准治疗时代,既往标准癌症治疗手段已证实与VTE形成密切相关,如手术、化疗以及抗血管生成靶向治疗等。当代基于程序性死亡受体及其配体(programmed cell death 1 or its ligand, PD-1/PD-L1)或细胞毒性T淋巴细胞抗原4(cytotoxic T-lymphocyte antigen 4,CTLA4)为治疗靶点的免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)的应用日趋成为常态并已成为指南推荐。然而,由ICIs诱导的各种非靶向自身免疫表现即免疫相关不良事件(immune-related adverse events, irAEs)不容忽视,其诱导的全身炎症对止血系统的影响迄今尚未得到适当研究。因此,临床医生非常有必要加强对ICIs相关VTE不良事件的认识。本文就ICIs相关VTE的发生率、危险因素、发病机制及临床管理原则等方面进行综述,以期为临床实践中免疫治疗相关静脉血栓的一级预防及精准治...     

免疫检查点抑制剂在软组织肉瘤中的应用：现状与展望

软组织肉瘤是一类少见的起源于间叶组织的除骨或软骨以外的恶性肿瘤，发病率低，但晚期转移患者通常缺乏有效的治疗手段，预后差，死亡率高。近年来，免疫检查点抑制剂(ICIs)在恶性肿瘤免疫治疗领域中取得了重要进展。在许多肿瘤中，ICIs有效改善了患者的预后，但在软组织肉瘤中，虽然有相关应用探索，却尚未获得高级别循证医学证据。本文总结了ICIs在软组织肉瘤临床治疗中的进展，包括ICIs单药及与其他治疗手段的联合使用，探讨了ICIs在未来软组织肉瘤治疗中的研究方向，希望为相关临床工作者提供参考。     

肿瘤免疫治疗后心脏事件的处理现状及剖析

免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)给肿瘤患者带来生存获益的同时,伴随而来的是可能发生全身各组织、脏器的免疫相关性毒副反应(immune-related adverse events, irAEs)。但irAEs发病机制还不明确,也缺乏确诊的检查手段,目前诊断irAEs还是使用排他性诊断方法,特别是临床医师诊治致死风险高的心脏毒性时存在很多疑惑。本文总结肿瘤患者ICIs治疗后出现的常见心脏问题,通过病历分析的方式,梳理如何甄别这些心脏问题是否是ICIs相关的心脏毒性、相应的临床处理决策及方法,以供临床医生参考。     

免疫检查点抑制剂的风湿性免疫相关不良反应与治疗

免疫检查点抑制剂（ICIs）在癌症治疗中显示出较好的疗效，但随着ICIs的快速应用，免疫相关不良事件（irAE）也越来越引起人们的关注。几乎全身器官皆可发生irAE，但风湿性irAE似乎具有不同的临床特征。本文就ICIs治疗引起的风湿性irAE的流行病学、临床特征及管理原则进行综述，并探讨其可能的潜在致病机制。     

免疫检查点抑制剂致孤立性促肾上腺皮质激素缺乏症患者的临床特征分析

目的：探讨免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）导致孤立性促肾上腺皮质激素缺乏症（isolated adrenocorticotropic hormone deficiency,IAD）患者的临床特征，为早期发现ICIs导致的内分泌免疫相关不良事件提供理论依据。方法：通过截至2022年7月检索万方、维普、中国知网、PubMed、Web of Science、Embase、Cochrane Library数据库，共纳入文献54篇，收集的70例患者中男性51例、女性19例，年龄为34～87岁，平均年龄（64.17±11.33）岁，收集使用ICIs导致IAD患者的临床资料进行统计学分析。结果：与IAD最相关的肿瘤类型为非小细胞肺癌35.7%(25/70)，其次为恶性黑色素瘤24.3%(17/70)。最常见导致IAD的ICIs为程序性细胞死亡-1(programmed cell death-1,PD-1)抑制剂87.1%(61/70)。使用PD-1、程序性细胞死亡-1配体（programmed cell death-ligand 1,PD-L1）...     

Cardiac imaging techniques for the assessment of immune checkpoint inhibitor-induced cardiotoxicity and their potential clinical applications

Immune checkpoint inhibitors (ICIs) have encouraged a paradigm shift in the clinical management of patients with cancer. Despite the dramatically improved tumor response and patient prognosis, ICIs have been associated with ICI-related myocarditis, which has a high fatality rate. Cardiac imaging plays a critical role in the assessment of cardiac injury. Echocardiography, cardiac magnetic resonance imaging, and targeted tracer-based cardiac molecular imaging techniques alone or in combination reflect pathophysiology and depict different aspects of lesions at different clinical stages, i.e., they have potentially complementary value. Imaging techniques for identifying ICI-induced cardiotoxicity at the early stage may reduce the incidence of adverse cardiovascular events. Particularly in planned ICI therapy among patients with cancer, improved monitoring approaches to identify patients who are at the highest risk of ICI-related myocarditis may help in refining clinical decisions, allowing treatment to be more accurately targeted toward patients who are most likely to benefit. In this study, we systematically reviewed the studies on cardiac imaging techniques for assessing ICI-induced cardiotoxicity. We elaborated about the potential applications of cardiac imaging techniques for the optimized management of patients with ICI-related myocarditis, including risk stratification, diagnosis, and prognosis.     

Predictors of the Onset of Type 1 Diabetes Obtained from Real-World Data Analysis in Cancer Patients Treated with Immune Checkpoint Inhibitors

Medications that target programmed cell death protein-1 (PD-1) have proven effective. However, blockade of PD-1/Programmed death-ligand 1(PD-L1) causes immune-related adverse events (irAEs). Characteristics of this irAE include many symptom, low in frequency, and difficulty in prevention. The key to a successful ICI-related treatment lies in the management of irAEs resulting from immune checkpoint inhibitor (ICI) treatment. Although it is difficult to predict irAE, we tried to extract features of irAE expression from analysis of real-world database. This study used data extracted from the Japan Adverse Drug Event Report (JADER) database to assess risk factors associated with serious side effects of irAE, type 1 diabetes (T1DM). The analysis targets were nivolumab, atezolizumab, durvalumab, and pembrolizumab, and the study period was from July 2014 to June 2019. Analysis of Japanese population data confirmed that being women and having melanoma were risk factors for developing ICI-related T1DM. Analysis using this database in combination with information on ICI-related T1DM provides information and guidelines that will help in the safer treatment of ICI in the future.     

Case report and brief review: IL-2-induced myocarditis

High dose bolus interleukin 2 (IL-2) used in the treatment of metastatic melanoma and renal cell carcinoma is known to have the potential for serious cardiac toxicity. At our institution 2 of 57 (3.5%) patients developed IL-2 induced myocarditis. The constellation of electrocardiographic changes and elevated troponin I is the hallmark of myocarditis. In this setting of high dose IL-2 therapy it is important to keep myocarditis in the differential in addition to the more frequently sought diagnosis of acute myocardial infarction. Although the gold standard for diagnosis is endomyocardial biopsy, there is considerable false negative rate. It may be reasonable to make the diagnosis on clinical grounds, while providing supportive care. Future investigation is required to better understand the pathophysiology and what factors may influence expression of this toxicity.     

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。     

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune‐related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life‐threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI‐associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI‐associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The “Checkpoint Inhibitor Safety Working Group,” a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI‐associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI‐associated myocarditis in patients with cancer.     

Serious Cutaneous Toxicities with Immune Checkpoint Inhibitors in the U.S. Food and Drug Administration Adverse Event Reporting System

Cutaneous toxicities frequently occurred with immune checkpoint inhibitors (ICIs), although clinical and pharmacological features are incompletely characterized. The U.S. Food and Drug Administration Adverse Event Reporting System was queried to describe ICI-related cutaneous toxicities, focusing on severe cutaneous adverse reactions (SCARs): Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. As compared with other anticancer drugs, a higher proportion of death (11.3% vs. 8.7%) and serious reports (42.7% vs. 34.6%) emerged for ICIs (p < .05). A higher frequency of coreported allopurinol and antiepileptics was recorded among 2,525 total SCARs (17% vs. 10%, ICIs and anticancer agents, respectively; p < .05). Mean times to onset were 47, 48, and 40 days (SJS, TEN, and DRESS, respectively), with comparable mean latency between monotherapy and combination regimens (41 days). This immune-related pattern advocates for long-lasting monitoring by oncologists and dermatologists.     

Association between immune checkpoint inhibitor-induced myocarditis and concomitant use of thiazide diuretics

Although an association has been reported between diuretics and myocarditis, it is unclear whether the risk of immune checkpoint inhibitor (ICI)-induced myocarditis is affected by concomitant diuretics. Thus, the aim of this work was to evaluate the impact of concomitant diuretics on ICI-induced myocarditis. This cross-sectional study used disproportionality analysis and a pharmacovigilance database to assess the risk of myocarditis with various diuretics in patients receiving ICIs via the analysis of data entered into the VigiBase database through December 2022. Multiple logistic regression analysis was performed to identify risk factors for myocarditis in patients who received ICIs. A total of 90 611 patients who received ICIs, including 975 cases of myocarditis, were included as the eligible dataset. A disproportionality in myocarditis was observed for loop diuretic use (reporting odds ratio 1.47, 95% confidence interval [CI] 1.02-2.04, P = .03) and thiazide use (reporting odds ratio 1.76, 95% CI 1.20-2.50, P < .01) in patients who received ICIs. The results of the multiple logistic regression analysis showed that the use of thiazides (odds ratio 1.67, 95% CI 1.15-2.34, P < .01) was associated with an increased risk of myocarditis in patients who received ICIs. Our findings may help to predict the risk of myocarditis in patients receiving ICIs.     

Cardiotoxicity of Immunotherapy: Incidence,Diagnosis, and Management

Purpose of review

This review describes cardiotoxicity associated with adoptive T cell therapy and immune checkpoint blockade.

Recent findings

Cardiotoxicity is a rare but potentially fatal complication associated with novel immunotherapies. Both affinity-enhanced and chimeric antigen receptor T cells have been reported to cause hypotension, arrhythmia, and left ventricular dysfunction, typically in the setting of cytokine release syndrome. Immune checkpoint inhibitors are generally well-tolerated but have the potential to cause myocarditis, with clinical presentations ranging from asymptomatic cardiac biomarker elevation to heart failure, arrhythmia, and cardiogenic shock. Electrocardiography, cardiac biomarker measurement, and cardiac imaging are key components of the diagnostic evaluation. For suspected myocarditis, endomyocardial biopsy is recommended if the diagnosis remains unclear after initial testing.

Summary

The incidence of immunotherapy-associated cardiotoxicity is likely underestimated and may increase as adoptive T cell therapy and immune checkpoint inhibitors are used in larger populations and for longer durations of therapy. Baseline and serial cardiac evaluation is recommended to facilitate early identification and treatment of cardiotoxicity.

     

Reconsidering Dexamethasone for Antiemesis when Combining Chemotherapy and Immunotherapy

Whether the immune suppressive action of glucocorticoid steroids, such as dexamethasone, might reduce the benefits of cancer immunotherapy has long been a concern. Observations that established tumor regressions in response to immune checkpoint inhibitors (ICIs) often persist, despite the use of steroids to mitigate ICI-related autoimmune breakthrough, are not sufficiently reassuring, because these observations do not address the potential blunting of immune priming at the initiation of ICI therapy. With increasing indications for ICI in combination with chemotherapy, this issue merits reconsideration. Professional society guidance advises that dexamethasone should be used as first-line prophylaxis for nausea and vomiting in patients receiving ICI and highly emetogenic chemotherapy combination regimens. Here, we review the availability of data on this subject and propose an alternative approach focused on the adoption of steroid minimization or sparing for prophylaxis of nausea until the underlying immune biology is better understood.     

基于数据库分析免疫检查点抑制剂相关不良事件在中国人群中的现状

目的:描述中国人群中免疫检查点抑制剂（ICI）相关不良事件（AEs）的状况。方法:截止至2019年9月22日，检索PubMed、Web of Science和Embase数据库中所有ICI相关的临床试验，入组中国患者或主要是中国人群的试验将会被纳入本研究，汇总并比较治疗相关不良事件（TRAE）和免疫相关不良事件（irAE）的发生率。结果:纳入13个试验合计1 063例患者，其中922（86.7％）例接受ICI单药治疗，141（13.3％）例接受ICI联合化疗或抗血管生成治疗。在所有患者中，任意级别的TRAE、1-2级TRAE、3-5级TRAE、任意级别irAE、1-2级irAE、3-5级irAE的累计发生率分别为84.1％、63.3％、20.9％、43.3％、40.0％、3.0％；与ICI单药治疗相比，ICI联合化疗或抗血管治疗显著提高了3-5级TRAE（46.1％ vs 17.0％，P＜0.001）和3-5级irAE（7.1％ vs 2.0％，P=0.015）。通过比较不同ICI之间的毒性谱，我们发现了一些药物特异性不良反应。结论:ICI相关的不良事件一般为轻度，中国人群耐受性良好。但是，当ICI与化疗或抗血管治疗联合使用时，3-5级的TRAE和irAE会显著增加。