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。     

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。     

免疫检查点抑制剂治疗的肝脏毒性管理

免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）在肿瘤领域取得了令人瞩目的疗效，使肿瘤治疗进入免疫治疗的新时代。但随着ICIs的广泛使用，免疫相关不良事件（immune-related adverse events，irAEs）也随之而来。肝脏是人体重要的代谢和消化器官，ICIs引起的肝脏不良事件应引起临床医师的关注。早发现、早诊断、规范治疗是改善预后的关键。本文简述irAEs的发病现状和可能机制，对现有的免疫相关肝脏毒性管理进行总结。     

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。     

PD-1/PD-L1免疫检查点抑制剂对右心室功能的影响

目的:采用二维斑点追踪技术评估PD-1/PD-L1免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)对肿瘤患者右心室功能的影响.方法:选择2018年6月至2020年11月在天津医科大学第二医院泌尿外科和肿瘤科住院的肿瘤患者46例,患者均未使用过ICIs,且进一步需要ICIs治疗.患者...     

放疗联合免疫治疗在非小细胞肺癌中的研究进展

近年来,免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）发展迅速,但单药治疗时获益人群有限。基于放疗和ICIs的协同作用机制,以及PACIFIC研究的阳性试验结果,一系列关于放疗联合免疫治疗（combined radiotherapy and immunotherapy,IRT）的临床研究在非小细胞肺癌（non-small cell lung cancer,NSCLC）中相继展开并取得满意的结果,但研究组合形式各异,对于最佳组合方案仍无定论。本文将系统总结该治疗模式的联合作用机制、最新临床研究进展及相关研究热点问题,以期为IRT模式在NSCLC中的临床应用提供参考。     

免疫检查点抑制剂相关甲状腺毒症

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)是近年来恶性肿瘤治疗领域的一项重大突破.其通过针对T细胞的调节作用,增强抗肿瘤免疫反应,改善恶性肿瘤患者的预后,延长患者生存期,现已获批用于治疗多种肿瘤,但ICIs在应用过程中产生的甲状腺毒症是不容忽视的临床问题.本文对ICIs相关甲...     

可溶性生长刺激表达基因2蛋白对免疫检查点抑制剂相关心肌炎预后的预测价值

目的:探讨可溶性生长刺激表达基因2蛋白(soluble growth stimulation expressed gene 2 protein,sST2)对免疫检查点抑制剂相关心肌炎(immune checkpoint inhibitor-associated myocarditis,ICIAM)患者预后的预测价值.方...     

免疫检查点抑制剂相关肺炎

<正>免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)相关呼吸系统不良事件表现有ICI相关肺炎(immune checkpoint inhibitor-related pneumonitis,ICIP)、胸腔积液、结节样病变等。ICIP是一种在ICIs使用后引起的治疗相关肺损伤,在胸部影像学检查中可以被观察到。ICIP伴或不伴有新出现浸润相关的呼吸系统症状/体征,主要表现为呼吸困难、咳嗽、发热、胸痛,甚至死亡。影像学可表现不同,最常见为磨玻璃影至大片实变和间质改变(网格影、纤维条索、牵拉性支气管扩张等),大部分累及双侧肺叶,同时可伴有胸腔积液。病理学主要表现为机化性肺炎,但不包括痰和/或支气管肺泡灌洗(bronchoalveolar lavage,BAL)检测的新发感染及肿瘤进展^[2]。ICIP在所有免疫相关不良事件(immunerelated adverse events,ir AEs)致死原因中排名第一位。     

免疫检查点抑制剂相关垂体功能减退临床特征

目的 探讨免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）诱发的垂体功能减退的临床特征。方法 回顾性纳入2019年1月至2022年6月在复旦大学附属中山医院内分泌科诊治的使用ICIs后出现垂体功能减退的各类肿瘤患者，分析ICIs相关垂体功能减退的临床表现、实验室检查结果、影像学特征。结果 共纳入23例患者，其中男性13例（53.5%）、女性10例（43.5%），平均年龄（59.5±11.8）岁。ICIs包括程序性死亡受体1(PD-1)单抗和细胞毒T淋巴细胞相关抗原4(CTLA-4)单抗。23例患者均出现继发性肾上腺皮质功能减退，均未出现中枢性尿崩症。累及垂体-甲状腺轴者3例（13.0%）；甲状腺功能正常者11例（47.8%）；出现ICIs相关原发性甲状腺功能减退9例（39.1%）。累及垂体-性腺轴者4例（17.4%）。结论 ICIs相关垂体功能减退主要表现为继发性肾上腺皮质功能减退，部分累及垂体-甲状腺轴、垂体-性腺轴，也可同时出现甲状腺腺体损伤，表明及时评估ICIs治疗中患者的垂体及靶腺功能有助于提高免疫治疗的安全性。     

免疫检查点抑制剂相关心肌炎的诊治进展

免疫调节是控制恶性肿瘤进展的重要决定因素,免疫检查点抑制剂(ICIs)的应用为恶性肿瘤治疗带来突破性进展,很大程度上改善了患者的生存时间和生活质量,然而不可避免的是,其也带来免疫相关不良反应(irAE)毒性风险。本文就ICIs相关心肌炎的发病机制、发病率、诊断和治疗策略进行综述。     

Immune checkpoint blockade as a potential therapeutic target in non-small cell lung cancer

ABSTRACT

Introduction: The recent emergence of immune checkpoint blockade therapy and the progression of immunobiology in cancer have spurred an increasing interest in the immunotherapy for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs), designed to directly target immune inhibitory molecules, have demonstrated efficacy in the treatment of patients with advanced NSCLC.

Areas covered: In the present article, the authors summarize the mechanism, efficacy and safety of major ICIs for the treatment of advanced or metastatic NSCLC. Combinations of different ICIs or conventional therapy and/or targeted agents for NSCLC treatment in clinical trials are also updated. In addition, immune-related adverse events and the roles of inhibitory immune checkpoint molecules as potential biomarkers in the immune checkpoint blockade therapy for NSCLC are emphatically elucidated.

Expert opinion: Immunotherapies targeting the immune checkpoint pathways have shown potential to generate durable responses and improve survival for NSCLC patients. Although the toxicity profile of this immunotherapy is manageable, immune-related adverse events and drug resistance may cause therapeutic failure. Therefore, a better understanding of the mechanisms underpinning its function and the potential side effects of ICIs, as well as the identification of predictive biomarkers for patient selection are essential.     

Predictive molecular markers for the treatment with immune checkpoint inhibitors in colorectal cancer

Colorectal cancer is one of the most common malignant tumors and, hence, has become one of the most important public health issues in the world. Treatment with immune checkpoint inhibitors (ICIs) successfully improves the survival rate of patients with melanoma, non‐small‐cell lung cancer, and other malignancies, and its application in metastatic colorectal cancer is being actively explored. However, a few patients develop drug resistance. Predictive molecular markers are important tools to precisely screen patient groups that can benefit from treatment with ICIs. The current article focused on certain important predictive molecular markers for ICI treatment in colorectal cancer, including not only some of the mature molecular markers, such as deficient mismatch repair (d‐MMR), microsatellite instability‐high (MSI‐H), tumor mutational burden (TMB), programmed death‐ligand‐1 (PD‐L1), tumor immune microenvironment (TiME), and tumor‐infiltrating lymphocytes (TILs), but also some of the novel molecular markers, such as DNA polymerase epsilon (POLE), polymerase delta 1 (POLD1), circulating tumor DNA (ctDNA), and consensus molecular subtypes (CMS). We have reviewed these markers in‐depth and presented the results from certain important studies, which suggest their applicability in CRC and indicate their advantages and disadvantages. We hope this article is helpful for clinicians and researchers to systematically understand these markers and can guide the treatment of colorectal cancer.     

Immunotherapy for non-small-cell lung cancer

Activation of the host immune system represents an attractive treatment approach for cancers. In non-small-cell lung cancer (NSCLC), a variety of immunotherapies, including nonspecific immune stimulants, vaccines and checkpoint inhibitors, have been evaluated in clinical trials. Several randomized Phase III trials have failed to demonstrate clinical benefit from nonspecific immune stimulants and vaccines in the overall trial populations. Activity of vaccines in subsets of patients in these trials needs further evaluation. Unlike vaccines aimed at stimulating a cellular immune response to antigens differentially expressed in cancers, checkpoint inhibitors aim at overcoming immune inhibitory signals in the tumor microenvironment via pharmacological inhibition of immune checkpoints – a crucial tumoral immune escape mechanism. Early clinical trials of checkpoint inhibitors showed promising results with some durable responses. Better understanding of the mechanisms of immunosuppression specific to NSCLC will be crucial for successful patient selection for immunotherapy.     

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...     

程序性死亡因子-1抑制剂在血液系统恶性肿瘤治疗中的研究进展

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用是一种新型免疫治疗手段。阻断程序性死亡因子-1(programmed death 1,PD-1)与其配体(PD-L1)结合,可避免免疫逃逸,恢复机体免疫应答,发挥其抗肿瘤效应,是目前抗肿瘤治疗中炙手可热的方法之一。PD-1抑制剂在越来越多的实体瘤治疗中表现出较好疗效,但在血液系统恶性肿瘤中的应用仍相对有限。本文回顾PD-1抑制剂在血液系统恶性肿瘤中的临床研究,探讨其临床应用前景。