晚期非小细胞肺癌的靶向治疗进展

晚期非小细胞肺癌以全身治疗为主,但化学治疗效果欠佳.近年来,非小细胞肺癌的致病靶点相继发现,新型治疗方式如靶向药物、免疫检查点抑制剂等得以应用,使晚期非小细胞肺癌患者的生存时间及生存质量都得到了极大改善.晚期非小细胞患者都推荐进行基因检测,以获取更精准的个体化治疗.该文就针对晚期非小细胞肺癌的不同类型基因突变以及对应的...     

肿瘤免疫治疗:回顾与展望

随着肿瘤免疫学的迅速发展, 免疫治疗逐渐引起肿瘤治疗领域专家的重视, 相关研究为晚期肿瘤患者提供了新的治疗机会。以程序性死亡受体1及其配体、细胞毒性T淋巴细胞相关抗原4为代表的免疫检查点抑制剂是目前晚期肿瘤临床治疗的研究热点, 已有多种免疫检查点抑制剂获得美国食品药品监督管理局批准用于晚期肿瘤免疫治疗, 其不仅安全性高, 且在晚期黑色素瘤、非小细胞肺癌、肾癌、尿路上皮癌、非霍奇金淋巴瘤中展现出令人振奋的治疗效果, 有效延长了患者生存期。嵌合抗原受体T细胞疗法也是目前免疫治疗领域的明星产品之一, 对急性白血病、非霍奇金淋巴瘤等血液系统恶性肿瘤展现出强大持久的治疗效果, 以Simpuleucel-T为代表的肿瘤疫苗曾一度成为肿瘤免疫治疗里程碑式的成功范例。肿瘤免疫治疗已取得了突破性进展, 研究前景不可估量。     

非小细胞肺癌免疫检查点抑制剂治疗病人症状评估量表的构建

目的:构建非小细胞肺癌免疫检查点抑制剂治疗病人症状评估量表，为临床实践提高症状管理效率提供依据。方法:通过文献回顾、德尔菲专家函询法和优序图法，筛选条目并确定条目的权重，构建非小细胞肺癌免疫检查点抑制剂治疗病人症状评估量表。结果:2轮专家函询问卷的有效回收率均为100%，专家权威系数为0.90，第1轮、第2轮的专家意见变异系数分别为0.12～0.35,0.07～0.25，肯德尔和谐系数分别为0.301,0.373(P<0.05)。构建的非小细胞肺癌免疫检查点抑制剂治疗病人症状评估量表包括6个维度，分别为呼吸-循环系统、消化系统、内分泌系统、神经-运动系统、皮肤系统及一般情况症状，共25个症状条目。结论:构建的非小细胞肺癌免疫检查点抑制剂治疗病人的症状评估量表具有较高的权威性和科学性，可作为非小细胞肺癌免疫检查点抑制剂治疗病人症状评估工具，为个性化的症状管理措施提供依据。     

免疫治疗在非小细胞肺癌治疗领域的应用

肺癌是全球范围内发病率排名第二的癌症,对人类身体健康造成了严重威胁。手术与放化疗是治疗肺癌的传统方案,虽具有一定的作用,但也存在诸如不良反应大、对患者耐受度要求较高、根治率低、易发生微小病灶转移等问题。近年来,随着各类免疫治疗方案出现,免疫检查点抑制剂的研发,免疫治疗这一全新思路也以单药治疗、联合化疗以及双药联合的新辅助免疫治疗形势被逐步应用于非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗,展现出明显优于传统治疗方案的治疗效果。本综述聚焦于非小细胞肺癌的免疫检查点抑制剂新辅助免疫治疗,从新辅助免疫治疗的各个应用角度出发全面探讨这一全新治疗思路对于治疗非小细胞肺癌的优势和重要意义。     

1例Nivolumab治疗非小细胞肺癌病人出现免疫相关性肺炎的护理

正肺癌位居我国恶性肿瘤发病率和死亡率第一位,每年新发病例达78.1万例[1],年死亡率过去20年每年上升7.7%,且未来5年仍呈上升趋势[2],其中最为常见的肺癌类型为非小细胞肺癌,约占总数的 80%～85%,由于早期症状的隐匿性大多数病人就诊时已是晚期[3]。晚期非小细胞药物治疗主要是化学治疗和靶向治疗。2018年6月15日我国首个程序性死亡受体1(programmed death 1,PD-1)免疫检查点抑制剂(PD-1单抗)正式获批     

非小细胞肺癌免疫检查点抑制剂治疗进展

肺癌是全球范围内发病率及死亡率极高的恶性肿瘤,其中以非小细胞肺癌(non-small cell lung cancer,NSCLC)最为常见。NSCLC的传统治疗主要依靠化学药物,近年来免疫治疗成为NSCLC治疗的热点,并取得了令人瞩目的进展。大量新型生物免疫制剂被开发并应用于临床,其中免疫检查点抑制剂的应用最广、疗效最为肯定。本文将对近年NSCLC免疫治疗生物标志物研究现状及进展进行阐述,以期提高免疫治疗精准度,更好地指导NSCLC患者的个体化治疗。     

小细胞肺癌的生物学研究及其临床治疗进展

肺癌是全球几大恶性肿瘤之一,在我国居于恶性肿瘤发病及死亡首位。小细胞肺癌是肺内分泌肿瘤的一种,具有侵袭性强、易复发、易转移、预后不良等特征。而临床上小细胞肺癌的一线治疗方案仍未取得突破性的进展,主要仍以化疗为主,辅以放疗等综合治疗。虽然,小细胞肺癌对化疗反应敏感,但80%局限期小细胞肺癌及几乎所有广泛期小细胞肺癌都会发生肿瘤复发及进展,且化疗的毒副作用大。生物信息学及分子生物技术的发展为癌症的诊治提供更为广泛的空间,其中生物治疗方法为近年研究的热点之一,尤其是免疫治疗,特别是研究一些免疫检查点抑制剂以达到抗癌的作用。本文旨在阐述小细胞肺癌生物学研究及其治疗进展。      

1例粪菌移植治疗晚期非小细胞肺癌病人免疫检查点抑制剂相关性肠炎合并艰难梭菌感染的护理

总结1例粪菌移植治疗晚期非小细胞肺癌病人免疫检查点抑制剂相关性肠炎合并艰难梭状芽孢杆菌(艰难梭菌)感染的护理经验。护理要点包括腹泻的护理、粪菌移植护理、营养护理、管道护理、血栓风险的护理、心理护理、延续性护理。经过精心的治疗及护理,病人住院19 d后腹泻好转出院,出院7 d后随访,未发生粪菌移植相关并发症。     

不同量表对SHR-1210联合阿帕替尼治疗晚期非小细胞肺癌致手足综合征患者的生活质量评估效果比较

正新型靶向治疗药物所致的手足综合征(handfoot syndrome,HFS)是一种极其常见的皮肤毒性反应,严重影响患者的生活质量。既往研究表明,阿帕替尼单药治疗晚期非小细胞肺癌(non-small-cell lung cancer,NSCLC)后HFS发生率较高,为24%～48%,其中3级以上毒性为4%～14%~([1-2])。2018年被称为中国免疫治疗元年,纳武利尤单克隆抗体和帕博利珠单克隆抗体分别于2018年6月和7月经国家食品药品监督管理局(China food and drug administration,CFDA)获批上市,同年12月国产免疫检查点抑制剂也相继获批。免疫检查点抑制剂相     

晚期非小细胞肺癌免疫治疗进展

肺癌是我国最常见的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)约占85%,且大部分NSCLC患者在确诊时疾病已进展至晚期,病死率较高。近年来,临床对于晚期NSCLC的治疗已从传统的手术治疗、化学治疗、放射治疗、靶向治疗走向了免疫治疗。免疫检查点抑制剂(ICIs)治疗晚期NSCLC体现出了良好的抗肿瘤活性,尤其体现在细胞毒性T淋巴细胞相关抗原-4(CTLA-4)、程序性死亡受体-1(PD-1)、程序性死亡配体-1(PD-L1)抑制剂。基于此,本文将重点综述CTLA-4、PD-1、PD-L1抑制剂在晚期NSCLC中的治疗进展,以期提高患者的临床获益率,为临床选择合理治疗方案提供参考。     

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.     

疗效预测生物标志物在去势抵抗性前列腺癌中的研究进展

免疫检查点抑制剂(ICIs)疗法在治疗多种晚期实体瘤中取得了革命性的突破,其中包括了去势抵抗性前列腺癌(CRPC).在过去几年中,已有多种ICIs应用于CRPC,并证明可改善患者的总生存期(OS),但是由于适用人群受限以及毒副作用大,大部分药物的临床获益很少是持久的.目前可预测ICIs在CRPC疗效的生物标志物仍欠缺可...     

Research status on immunotherapy trials of gastric cancer

The breakthrough of immune checkpoint inhibitor (ICI) therapy has created extensive opportunities for cancer immunotherapy. Especially, the block of programmed death-1/programmed death ligand 1 (PD-L1) axis using ICIs has become a new therapeutic strategy to treat advanced gastric cancer (GC). However, in the past decade, single-arm and randomized trials for single-drug ICI therapy showed that the therapeutic effect was not satisfactory, including clinical trials for advanced GC. However, after selecting suitable predictive biomarkers and developing a combination of anti-angiogenic targeted drugs and other chemotherapeutic drugs, the objective response rate and progression-free survival of patients with gastric cancer were improved significantly. The United States Food and Drug Administration has approved treatment with pembrolizumab for patients with advanced GC with PD-L1 expression or microsatellite instability-high/mismatch repair deficiency. In this review, the updated data from the latest trial results of combination immunotherapy for GC are presented. Based on the outcome of combination therapy, we discuss its possible molecular mechanism and summarize effective predictive biomarkers. We also discuss possible problems stemming from results of other clinical trials of ICI treatment and propose other directions for ICI therapy.     

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。     

Entinostat induces antitumor immune responses through immune editing of tumor neoantigens

Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti–PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell–autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.     

Rapid subcutaneous progression after immunotherapy in pretreated patients with metastatic carcinoma: two case reports

There is heterogeneity in cancer patients’ responses to immune checkpoint inhibitors (ICIs), including hyperprogression, which is very rapid tumor progression following immunotherapy, and pseudoprogression, which is an initial increase followed by a decrease in tumor burden or in the number of tumor lesions. This heterogeneity complicates clinical decisions because either premature withdrawal of the treatment or prolonged ineffective treatment harms patients. We presented two patients treated with ICIs with heterogeneous responses. One patient had Merkel cell carcinoma in the right thigh, and the other had nasopharyngeal squamous carcinoma. The first patient was treated with sintilimab and the second with sintilimab combined with abraxane. In the first patient, subcutaneous lesions grew substantially after the first cycle of treatment with sintilimab. In the second patient, subcutaneous lesions grew gradually after the second cycle of treatment with sintilimab combined with abraxane. In both cases, biopsy examination confirmed that newly emerged lesions were metastases of the primary tumor. These two cases remind clinicians that when subcutaneous nodules appear after treatment with ICIs, pathological biopsy is needed to determine the nature—pseudoprogression or rapid progression—of the disease course.     

Research progress and clinical application of predictive biomarker for immune checkpoint inhibitors

Introduction: Immune checkpoint inhibitors (ICIs) have emerged as epochal milestones in the ?eld of anti-cancer immunotherapy. With promising clinical effectiveness, ICIs can significantly prolong the overall survival of patients with advanced cancer of different types. Although their remarkable effectiveness has been demonstrated in clinical application, ICIs display limitations in terms of unique response patterns. Only a subset of patients exhibits objective responses, while others show rapid disease progression. Considering that there is a fair representation of both subsets of patients (responders and non-responders), clinicians ought to effectively stratify patients who will potentially benefit from ICI therapy, and optimize a strategy for patient selection.

Areas covered: In this review, the authors have summarized several key factors involved in the biomarker development of ICI therapy, such as neoantigen production and presentation, the tumor microenvironment, and alternation in specific gene signaling pathways.

Expert opinion: Considering the extreme complexity of the immune system, a single biomarker may fail to appropriately stratify patients for ICI therapy. Therefore, future biomarker research should focus on designing an integrated biomarker system that will successfully guide combination therapies to overcome resistance to immunotherapy.     

Non–Small Cell Lung Cancer: Epidemiology,Screening, Diagnosis,and Treatment

Lung cancer remains the leading cause of cancer deaths in the United States. In the past decade, significant advances have been made in the science of non–small cell lung cancer (NSCLC). Screening has been introduced with the goal of early detection. The National Lung Screening Trial found a lung cancer mortality benefit of 20% and a 6.7% decrease in all-cause mortality with the use of low-dose chest computed tomography in high-risk individuals. The treatment of lung cancer has also evolved with the introduction of several lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, and NTRK mutations. Similarly, immune checkpoint inhibitors (ICIs) have dramatically changed the landscape of NSCLC treatment. Furthermore, the results of new trials continue to help us understand the role of these novel agents and which patients are more likely to benefit; ICIs are now part of the first-line NSCLC treatment armamentarium as monotherapy, combined with chemotherapy, or after definite chemoradiotherapy in patients with stage III unresectable NSCLC. Expression of programmed cell death protein-ligand 1 in malignant cells has been studied as a potential biomarker for response to ICIs. However, important drawbacks exist that limit its discriminatory potential. Identification of accurate predictive biomarkers beyond programmed cell death protein-ligand 1 expression remains essential to select the most appropriate candidates for ICI therapy. Many questions remain unanswered regarding the proper sequence and combinations of these new agents; however, the field is moving rapidly, and the overall direction is optimistic.     

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。     

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。