肿瘤免疫检查点抑制剂相关肺炎的管理

以免疫检查点程序性死亡因子-1（programmed death 1，PD-1）抑制剂、程序性死亡因子配体-1（programmed death ligand 1，PD-L1）抑制剂及细胞毒性T淋巴细胞相关蛋白4（cytotoxic T lymphocyte antigen 4，CTLA-4）抑制剂为代表的肿瘤免疫治疗，近年来在肿瘤治疗中广泛开展，有效延长了肿瘤患者的生存期，但也可能导致免疫治疗相关不良事件（immune-related adverse events，irAEs）。免疫检查点抑制剂（immune checkpoint inhibitor，ICIs）相关肺炎是常见的irAEs之一，可导致部分肿瘤患者治疗暂停、治疗失败、甚至威胁生命。正确了解ICIs相关肺炎的临床特点，早期诊断并恰当治疗，对影响肿瘤患者的预后、延长生命有重要意义。     

免疫检查点抑制剂相关内分泌不良事件

免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）是一类新型抗肿瘤药物，通过增强抗肿瘤免疫应答产生抗肿瘤作用，已经在多种恶性肿瘤治疗中表现出显著疗效。由于免疫检查点抑制剂特定的作用靶点和机制，可引起自身免疫和炎症效应，称为免疫相关不良事件（immune-related adverse events，irAEs）。随着免疫检查点抑制剂的广泛应用，其导致的irAEs也越来越受到重视，其中内分泌相关不良事件（如甲状腺功能障碍、垂体炎、肾上腺功能不全等）起病时表现隐匿，不易被发现，导致治疗延误，往往带来严重不良后果甚至危及患者生命。本文将总结既往文献，对免疫检查点抑制剂相关内分泌不良事件的发生率、可能的发病机制、临床表现、诊断等进行述评。     

免疫检查点抑制剂相关关节病

<正>随着肿瘤免疫相关领域研究的不断进展,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)在癌症靶向治疗的应用愈发广泛,研究发现不少患者出现了不同程度的免疫相关不良事件(immunerelated adverse event,irAEs),相比于其他常见器官或系统发生的irAEs,ICIs相关关节病似乎有着其独特的临床特征。1分类及发病率1.1分类根据WHO的国际疾病分类(International Classification of Diseases 11^th version,ICD-11),传统的关节病主要分为：(1)骨关节炎,如膝关节炎、髋关节炎等;(2)感染相关性关节病;(3)炎性关节病,如类风湿关节炎、银屑病性关节炎、痛风性关节炎等;(4)其他类型关节病等。而现有研究报道,ICIs相关irAEs引起的关节病中,主要为炎性关节病^[1]及骨关节炎^[2]。     

PD-1单抗治疗后发生单侧眼肌麻痹1例报告

接受免疫检查点抑制剂（ICIs）治疗的患者常发生免疫相关不良事件（Immune-related adverse events，irAEs），但免疫相关眼不良事件（Ocular immune-related adverse events，oAEs）的发生率不足1%。我们报道1例的PD-1单抗在治疗淋巴瘤后发生的孤立性眼肌麻痹，这是完整记录oAEs发病及治疗前后MRI变化的报道。患者在接受帕博丽珠单抗（pembrolizumab）治疗6个月后出现复视，左眼外展受限，全身MRI提示同侧眶周肌肉增粗、未发现全身其他肌肉受累。经停用帕博丽珠单抗及中剂量泼尼松治疗后，患者眼部症状很快恢复正常。在临床症状缓解后21个月，患者病变的眼外肌在MRI上也完全恢复正常。临床医生需掌握oAEs遗留的MRI改变与肿瘤浸润的鉴别。发生oAEs后长期的影像随访是必要的。     

免疫检查点抑制剂相关心肌炎

<正>免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)引起的免疫相关不良事件(immunerelated adverse events,irAEs)可以累及身体任何器官,其导致的心肌炎是一种罕见且致命的并发症^[1]。据报道,ICIs相关心肌炎的发病率为0.04%～1.14%,是一种不常见的不良事件^[2],但其死亡率可高达25%～50%。RUBIOINFANTE^[3]的一项meta分析显示在4751例患者中,1.3%出现心脏irAEs,其中以心肌炎最常见(50.8%);一项回顾性分析中显示964例使用ICIs的患者中心肌炎发病率为1.14%^[4];SALEM等^[5]在世界卫生组织的全球个体病例安全报告数据库VigiBase中描述了2008—2018年报道的122例病例,该研究显示单独使用程序性死亡受体-1(programmed death-1,PD-1)/程序性死亡受体-配体1(programmed death-ligand 1,...     

免疫检查点抑制剂相关心肌炎临床诊疗实施建议

免疫检查点抑制剂（immune-checkpoint inhibitors，ICIs）现已应用于多种恶性肿瘤的治疗，为肿瘤患者带来获益的同时，其严重ICIs相关心肌炎日益为临床带来新挑战。本临床诊疗实施建议聚焦ICIs相关心肌炎的危险因素、诊断与鉴别诊断、临床分型及治疗、监测转归和治疗重启等关键临床问题，参考国内外相关共识或指南和新近发表的循证证据，结合实际临床经验，为ICIs相关心肌炎的诊疗提供具有实践性的指导意见和建议。     

免疫检查点抑制剂血液系统不良事件

<正>免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)包括程序性死亡受体-1 (programmed death-1,PD-1)单抗、程序性死亡受体-配体1 (programmed death-ligand 1,PD-L1)单抗和细胞毒性T淋巴细胞相关抗原-4(cytotoxic T-lymphocyte-associated protein-4,CTLA-4)单抗等,是通过抑制或阻断CTLA-4或PD-1等信号通路重新激活T淋巴细胞来识别癌细胞,从而达到抗肿瘤作用。随着ICIs的广泛应用,免疫治疗所致免疫耐受失衡导致免疫相关不良事件(immune-related adverse events,irAEs)得到关注及重视,内分泌器官、免疫系统器官、皮肤、肺、胃肠道相关不良事件较为常见,而血液系统不良事件的报告相对较少。对9324例使用ICIs的患者进行meta分析显示,贫血、中性粒细胞减少和血小板减少的发生率分别为9.8%、0.94%和2.8%^[1]。     

肿瘤免疫检查点抑制剂联合治疗策略及临床应用

目的：免疫检查点抑制剂（immune checkpoint inhibitions，ICIs）的应用显著改善了多种肿瘤的预后，是当前肿瘤治疗中备受重视的手段。以程序性死亡因子-1（programmed death 1，PD-1）、程序性死亡因子配体-1（programmed death ligand 1，PD-L1）和细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte antigen 4，CTLA-4）单克隆抗体为主的免疫检查点的临床研究结果显示，单一ICIs临床效果有限。不同ICIs的联合治疗、联合化疗及联合抗肿瘤血管生成药物可明显提高疗效，新发现的免疫检查点淋巴细胞激活基因-3（lymphocyte activation gene-3，LAG-3）、T细胞免疫球蛋白黏液素3（T cell immunoglobulin mucin-3，TIM-3）、T细胞免疫球蛋白和ITIM域（T cell immunoglobulin and ITIM domain，TIGIT）等抑制剂的转化和联合应用，对难治性或ICIs耐药患者的疗效值得期待。     

帕博利珠单抗相关爆发性心肌炎一例

免疫检查点抑制剂（ICIs）是近年来肿瘤治疗领域的最重要进展之一。随着ICIs适应证的不断拓展及国内原研药相继进入临床,ICIs将用于越来越多的肿瘤患者,然而ICIs的严重不良反应尚未引起临床医师的广泛关注。该文报道1例肝癌术后复发接受帕博利珠单抗治疗引起爆发性心肌炎的病例,患者主要表现为心肌酶升高,难治性心律失常,伴有肝损伤,呼吸衰竭等,虽经积极抢救最终死亡。该例提示ICIs相关免疫性心肌炎早期症状不典型,但疾病呈爆发性进展,需要临床医师早期识别,及早干预。     

免疫检查点抑制剂相关心肌炎分子机制研究进展

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）已成为目前应用最广的恶性肿瘤免疫疗法，主要包括CTLA-4（cytotoxic T lymphocyte associated antigen-4）抑制剂、PD-1/PD-L1（programmed death protein-1/ligand-1）抑制剂和LAG-3（lymphocyte activation gene-3）抑制剂。ICIs导致的最致命的免疫相关不良反应（immune-related adverse events, irAE）之一为免疫检查点抑制剂相关的心肌炎（immune checkpoint inhibitor-associated myocarditis, ICIAM）。ICIs联合治疗时ICIAM的发病率多高于单药治疗。其分子机制主要包括免疫检查点作为新抗原、肿瘤同源抗原的异位识别、免疫检查点心脏保护的阻断、自身抗体和炎症因子的产生以及微生物的调节作用等。目前已有多种治疗ICIAM药物及非药物性方案。对于ICIAM分子机制的探索和治疗管理方案的进步仍需多学科共同努力。     

肌减少症对实体瘤患者免疫检查点抑制剂治疗影响的meta分析

目的 探究肌减少症对免疫检查点抑制剂(immune checkpoint Inhibitor,ICIs)的短期疗效、远期预后和免疫相关不良反应的影响。方法 对PubMed、EMBASE和Cochrane数据库中在2021年6月前发表的关于肌减少症对免疫治疗的实体瘤患者短期疗效、远期预后和免疫相关不良反应影响的文献进行检索。采用Review Manager 5.3软件和Stata14.0软件进行统计分析。结果 共有27篇文献被纳入荟萃分析,Meta分析结果显示合并肌减少症可降低肿瘤患者免疫治疗的客观反应率(RR=0.11,95%CI:0.02～0.54)和疾病控制率(RR=0.55,95%CI:0.39～0.78)。同时,治疗前合并肌减少症是肿瘤患者预后不良的危险因素(OS:HR=1.60,95%CI:1.30～1.97;PFS:HR=2.81,95%CI:1.88～4.22),甚至在治疗期间肌减少也是患者预后不良的危险因素。合并肌减少症会增加患者发生严重免疫相关不良事件的风险(RR=1.27;95%CI:0.74～2.19)。结论 肌减少症是肿瘤患者免疫治疗效果和预后不佳的危险因素。     

免疫检查点抑制剂的抗肿瘤临床实践与展望

基于靶向免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的肿瘤免疫治疗在近10年取得了重要进展,程序性死亡因子-1(PD-1)/程序性死亡因子配体-1(PD-L1)抗体治疗则成为肿瘤治疗领域最具潜力的新型疗法.中国肿瘤学者与发达国家学者基本同步开展的肿瘤免疫疗法的临床实践,进一步验...     

老年肿瘤免疫检查点抑制剂临床治疗进展

免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)是当今肿瘤治疗领域的革命性突破, 改变了多种肿瘤治疗模式。老年人占肿瘤现患人数及死亡人数的绝大部分, 老年肿瘤患者存在免疫衰老、自身免疫性疾病及感染性疾病发生率高、肿瘤突变负荷与年轻患者存在差异等均可能影响ICIs疗效。在大部分ICIs临床试验中, 老年肿瘤患者在受试人群中未能占据应有比例, 亚组分析及荟萃分析结果提示年龄对疗效及免疫相关不良反应的发生影响较小。临床医生可参考相关试验数据, 在体能状态较好的老年肿瘤患者中使用ICIs, 以积累更多的真实世界数据。     

Dynamic changes in the radiologic manifestation of a recurrent checkpoint inhibitor related pneumonitis in a non-small cell lung cancer patient: A case report

BACKGROUNDAs immune checkpoint inhibitors (ICIs) have become widely used in lung cancer treatment, immune-related adverse events (irAEs) warrant sufficient attention. Checkpoint inhibitor-related pneumonitis (CIP) is one of the most concerning adverse events as it is uncommon but life threatening.CASE SUMMARYThe patient whose case is reported here experienced three episodes of CIP in a span of 4 mon. Interestingly, the three episodes of CIP involved different regions of the lung separately. Taking these pneumonitis areas together makes nearly a whole lung area.CONCLUSIONThis case showed that recurrent CIPs may occur repeatedly until the whole lung is involved, suggesting that the follow-up period of CIP should be long enough, and the rechallenge of ICI should be done with due caution.     

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 algo...     

Hepatotoxicity Associated with Immune Checkpoint Inhibitors in Clinical Practice: A Study Leveraging Data from the US Food and Drug Administration's Adverse Event Reporting System

PurposeImmune checkpoint inhibitors (ICIs) are a promising option for the treatment of patients with various cancers. Emerging case reports have raised awareness on hepatotoxicity, a potentially fatal adverse event (AE) that may be associated with the use of ICIs. This study assessed the potential association between ICIs and hepatotoxicity through the mining of data from the US Food and Drug Administration's AE Reporting System (FAERS).MethodsA total of 9,217,181 AEs reported in the period from quarter 1 of 2004 to quarter 3 of 2021 were assessed. Information components (ICs) and reporting odds ratios (RORs) were used to evaluate the association between the use of ICIs and hepatotoxicity.FindingsA total of 52,463 AE reports listed ICIs, used alone or in combination, as a suspected drug. Of these, 1481 cases were related to both ICIs and hepatotoxicity. The use of ICIs was significantly associated with hepatotoxicity compared to all other drugs, making it a safety signal (IC = 1.43 [95% CI, 1.36–1.51]; ROR = 2.78 [95% CI, 2.64–2.93]). With monotherapy, all ICIs, except tremelimumab, were associated with liver damage. The most commonly prescribed combination therapy was nivolumab + ipilimumab (321 cases) with a significant signal detected. Notably, ICI use was significantly associated with hepatic failure (IC = 1.24 [95% CI, 1.06–1.42]; ROR = 2.40 [95% CI, 2.13–2.72]). The risk for ICI-associated hepatotoxicity (including hepatic failure) was greater with ICI combination therapy than with ICI monotherapy. All subgroups by sex and age also showed significant associations between ICI use and hepatotoxicity.ImplicationsA significant association was detected between ICI use and hepatotoxicity. The risk for hepatotoxicity (including hepatic failure) was greater with ICI combination therapy compared with ICI monotherapy.     

PD-1抑制剂免疫相关不良反应的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICI)的应用是肿瘤治疗领域的重大突破,是恶性肿瘤患者新的选择和希望。国家食品与药品管理监督局(Chinese Food and Drug Administration,CFDA)批准程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)免疫抑制剂用于多种肿瘤的治疗。但是PD-1抑制剂可引起自身免疫毒性,虽然大多数免疫相关不良反应(immune-related adverse events,irAEs)以1~2级为主,但仍有部分患者发生危及生命的3~4级免疫毒性反应。