免疫检查点抑制剂在非小细胞肺癌临床诊疗中的研究进展

肺癌是目前世界上发病率和死亡率最高的恶性肿瘤, 其中主要的类型是非小细胞肺癌(NSCLC)。免疫检查点抑制剂是恶性肿瘤治疗发展史上里程碑式的发现, 给很多恶性肿瘤患者提供了新的治疗选择。文章总结了免疫检查点抑制剂在NSCLC临床诊疗中的研究进展, 探讨了药物作用的原理、不同临床分期NSCLC的诊疗差别以及未来的研究方向, 为临床医师在治疗过程中使用免疫检查点抑制剂提供参考。     

多肽药物在肿瘤免疫治疗中的研究进展

免疫治疗是当前最受关注的肿瘤治疗方式之一,免疫检查点抑制剂、细胞治疗和肿瘤疫苗等免疫治疗手段,在临床上取得了重要进展。近年来,除了以单抗药物为代表的免疫检查点抑制剂以外,多肽药物也逐渐受到关注。本文着重总结多肽药物在免疫检查点抑制剂方面的研究进展及应用,包括单靶点多肽阻断剂、双功能多肽阻断剂、自组装多肽,以及免疫检查点多肽在肿瘤诊断中的应用等,并对多肽药物目前面临的瓶颈问题提出思考,为多肽药物在肿瘤免疫治疗中的应用提供新的思路。     

免疫检查点抑制剂在EGFR突变非小细胞肺癌治疗应用的研究进展

目前,表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)是表皮生长因子受体(epidermal growth factor receptor,EGFR)基因敏感突变晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的一线治疗标准,但大多数患者最终出现获得性耐药。而针对免疫检查点程序性死亡受体(programmed death-1,PD-1)及其配体(PD-1 ligand,PD-L1)的抑制剂取得突破性进展,改变了NSCLC的治疗模式。多项研究显示,EGFR敏感突变NSCLC患者免疫检查点抑制剂疗效不佳,其可能机制主要包括EGFR敏感突变患者PD-L1的低表达、抑制性免疫微环境、低肿瘤突变负荷等等。通过对EGFR突变NSCLC患者特殊人群的选择,免疫检查点抑制剂与其他药物的联合应用,可能为EGFR敏感突变NSCLC患者的治疗带来希望。本文将对此进行综述,以期为表皮生长因子受体突变的非小细胞肺癌患者的治疗带来新的希望。     

放疗联合免疫检查点抑制剂在非小细胞肺癌中的临床研究进展

肺癌是癌症相关死亡病因最高的恶性肿瘤,其中非小细胞肺癌（NSCLC）约占所有肺癌的85%,超过50%的NSCLC患者确诊时伴有远处转移。NSCLC的综合治疗需要采用手术、放疗、化疗、靶向治疗及免疫检查点抑制剂等方式。放疗作为传统治疗手段之一,在各期NSCLC的治疗中均发挥着重要作用,其免疫调节效应备受关注;免疫检查点抑制剂（ICIs）的应用显著改善了晚期和局部晚期NSCLC患者的预后,但获益人群有限。目前放疗联合ICIs的治疗模式成为研究热点,本文就放疗联合ICIs在NSCLC治疗中的研究进展作一综述。     

药物选择剂量分割顺序对放疗联合免疫治疗晚期非小细胞肺癌疗效的影响

非小细胞肺癌(non-small cell lung cancer,NSCLC)约占肺癌总数的85％,53％的患者在确诊时即为晚期.近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)在晚期肿瘤治疗中效果显著.放疗在晚期NSCLC主要用于局部姑息治疗.研究显示免疫治疗协同放疗治...     

非小细胞肺癌胸部放疗联合免疫治疗研究进展

非小细胞肺癌(NSCLC)放疗联合免疫治疗,特别是联合PD-1/PD-L1免疫检查点抑制剂治疗,已成为近年来的研究焦点。探索放疗与免疫治疗的最优空间组合模式,实现各期患者最大限度的获益,是目前临床研究的方向之一。本文对放疗对肿瘤免疫环境的影响、各期NSCLC放疗联合免疫治疗进展以及存在的问题进行综述。     

放疗联合免疫检查点抑制剂治疗Ⅲ期不可切除非小细胞肺癌研究进展

长期以来,同步放化疗都是Ⅲ期不可切除的非小细胞肺癌(NSCLC)的标准治疗模式。但近 20年来,同步放化疗的疗效一直没有显著提高。近 2~3年来免疫检查点抑制剂在晚期肺癌中的地位不断提升,临床前及临床研究也证实了放疗与免疫检查点治疗具有协同作用。近来部分临床研究结果提示该治疗模式在Ⅲ期不可切除NSCLC中显著提高了疗效。本文综述 2017年以来最新临床研究,探讨放疗联合免疫检查点治疗联合模式在局部晚期NSCLC中的治疗价值。     

非小细胞肺癌免疫治疗进展

在过去十年中，非小细胞肺癌(non-small cell lung cancer, NSCLC)治疗经历了重大转变。对肺癌生物学机制更深入的了解促进了免疫治疗的发展，免疫检查点抑制剂(immunocheckpoint inhibitor, ICIs)在NSCLC的治疗中显示出巨大的益处，目前已成为晚期NSCLC患者不可或缺的治疗手段。同时，新型免疫治疗方案快速发展，因此，为了更好了解全世界范围内免疫治疗在NSCLC中的应用趋势，本文全面系统回顾了以免疫检查点抑制剂(ICIs)为代表的免疫治疗的临床研究进展，同时总结了新型免疫治疗疗法的应用进展，以期为免疫治疗NSCLC患者提供更多可借鉴应用成果。     

非小细胞肺癌的联合免疫治疗现状

对于晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）的患者来说,化疗、放疗、靶向治疗及抗血管生成治疗虽然可以改善其预后,但经相关研究发现,NSCLC患者的5年生存率仍不尽人意。近年来以程序性死亡蛋白1（programmed cell death protein 1,PD-1）/程序性死亡蛋白配体1（programmed death-ligand 1,PD-L1）抑制剂为代表免疫检查点抑制剂的出现为晚期NSCLC患者的治疗带来了新的希望。探索免疫检查点抑制剂联合化疗、抗血管生成药物、放疗的各项治疗策略是目前肿瘤界的热门话题,本文将对NSCLC联合免疫治疗的现状进行总结与讨论。     

三种新兴的免疫检查点分子在肿瘤免疫治疗中的研究进展

免疫检查点作为体内的“刹车分子”,与肿瘤的增殖、侵袭、转移及患者预后评估紧密相关,是良好的肿瘤治疗靶点。现有的免疫检查点阻断剂在非小细胞肺癌、黑色素瘤等恶性肿瘤上表现出较好疗效,但随之而来的免疫治疗相关不良反应也很突出。因此,寻找新的免疫检查点分子成为近年的研究热点。B7族同源体3（B7 Homolog 3,B7-H3）、T细胞免疫球蛋白和ITIM域（T cell immunoglobulin and ITIM domain,TIGIT）、肿瘤坏死因子受体2（tumor necrosis factor receptor 2,TNFR2）作为新兴的免疫检查点分子在肿瘤免疫治疗领域备受瞩目,本文将对其分子特性及相关研究进展进行综述。     

非小细胞肺癌过继细胞免疫治疗的研究进展

目前非小细胞肺癌发病率高,预后差,需要研究新的治疗方法。肿瘤的发生、发展和转移与人体免疫系统密切相关,过继输注免疫细胞是免疫治疗的一种方法,能够显著提高机体免疫系统的抗肿瘤效应。过继输注的免疫细胞多样,如 LAK、TIL、NK、γδ T、CIK、CTL 等,通过输注不同的免疫细胞或联合其他治疗介导靶细胞凋亡,可增强抗肿瘤效应。本文介绍各种免疫细胞的抗肿瘤的机制并回顾近几年治疗非小细胞肺癌的相关试验研究。     

Immune Checkpoint Inhibitors in EGFR-Mutated NSCLC: Dusk or Dawn?

Although immune checkpoint inhibitors (ICIs) that target programmed cell death protein-1/programmed cell death ligand-1 axis have significantly shifted the treatment paradigm in advanced NSCLC, clinical benefits of these agents are limited in patients with EGFR-mutated NSCLC. Several predictive biomarkers (e.g., programmed cell death ligand-1 expression, tumor mutation burden), which have been validated in EGFR-wild type NSCLC, however, are not efficacious in EGFR-mutated tumors, suggesting the unique characteristics of tumor microenvironment of EGFR-mutated NSCLC. Here, we first summarized the clinical evidence on the efficacy of ICIs in patients with EGFR-mutated NSCLC. Then, the cancer immunogram features of EGFR-mutated NSCLC was depicted to visualize the state of cancer-immune system interactions, including tumor foreignness, tumor sensitivity to immune effectors, metabolism, general immune status, immune cell infiltration, cytokines, and soluble molecules. We further discussed the potential subpopulations with EGFR mutations that could benefit from ICI treatment. Lastly, we put forward future strategies to adequately maximize the efficacy of ICI treatment in patients with EGFR-mutated NSCLC in the upcoming era of combination immunotherapies.     

The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC

Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types.     

Research Progress in Immunotherapy of NSCLC With EGFR-Sensitive Mutations

Lung cancer is a malignant tumor with high incidence and mortality across the world. The use of immune checkpoint inhibitors for lung cancer has improved the prognosis of some lung cancer patients to a greater extent and provided a new direction for the clinical treatment of lung cancer. Immunotherapy still has limitations in terms of its appropriate population and adverse reactions. Particularly for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation, there has been no major breakthrough in current immunotherapy. Whether immunotherapy can bring new benefits after drug resistance is induced by tyrosine kinase inhibitor-targeted therapy and whether the combination of immunotherapy with other treatments can improve the prognosis remain to be studied in depth. In this article, we provide a detailed review of the relevant characteristics of the tumor microenvironment of NSCLC with EGFR mutation and the current research on immunotherapy for NSCLC with EGFR mutation.     

Research Progress in Immunotherapy of NSCLC With EGFR-Sensitive Mutations

Lung cancer is a malignant tumor with high incidence and mortality across the world. The use of immune checkpoint inhibitors for lung cancer has improved the prognosis of some lung cancer patients to a greater extent and provided a new direction for the clinical treatment of lung cancer. Immunotherapy still has limitations in terms of its appropriate population and adverse reactions. Particularly for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation, there has been no major breakthrough in current immunotherapy. Whether immunotherapy can bring new benefits after drug resistance is induced by tyrosine kinase inhibitor-targeted therapy and whether the combination of immunotherapy with other treatments can improve the prognosis remain to be studied in depth. In this article, we provide a detailed review of the relevant characteristics of the tumor microenvironment of NSCLC with EGFR mutation and the current research on immunotherapy for NSCLC with EGFR mutation.Key words: Non-small cell lung cancer (NSCLC), Immunotherapy, Epidermal growth factor receptor (EGFR)-sensitive mutations     

驱动基因阴性晚期非小细胞肺癌脑转移免疫微环境及免疫治疗的研究进展

远端转移是晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者难以避免的并发症,脑转移（brain metastases,BM）是此类患者最常见的转移部位之一。脑转移患者可能出现头痛、视物模糊、偏瘫、肢体麻木等症状,生存质量受到严重影响。脑转移患者通常预后较差,自然中位生存期仅有3个月左右。传统上,针对驱动基因阴性NSCLC脑转移的治疗策略有局部干预的外科手术、放射治疗及系统性干预的化疗等,而有明确基因突变如EGFR、ALK、ROS1等的患者可采用新一代靶向药物治疗,但两类患者颅内治疗疗效均欠佳。免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）的出现为晚期肺癌的治疗带来新希望,其在黑色素瘤及肺癌脑转移患者中观察到了一定疗效。脑转移瘤的血管与正常脑血管存在显著差异。不同于肺部原发病灶,脑转移瘤具有独特的肿瘤微环境、免疫细胞特征及血管结构,无论是免疫单药治疗还是免疫联合治疗对肺癌脑转移患者均有效。由于难以获得脑组织样本,免疫治疗的生物标志物的研究受到限制。除了肿瘤细胞程序性死亡-配体1（programmed cell death ligand-1,PD-L1）外,肿瘤突变负荷（tumor mutation burden,TMB）可能是预测免疫治疗疗效的潜在生物标志物。本文梳理脑部肿瘤的微环境特征,回顾ICIs治疗相关研究进展,拟为驱动基因阴性NSCLC脑转移患者的治疗提供参考。      

Cancer vaccines for the treatment and prevention of non small-cell lung cancer

Cancer vaccines targeting non small-cell lung cancer (NSCLC) have been studied for decades; clinical trials, for the most part, have focused on the use of autologous and allogeneic whole-tumor cell vaccines. Recent advances in molecular biology and immunology, however, have allowed the identification of many tumor antigens involved in the generation of immunity to NSCLC. Although small-cell lung cancer (SCLC) is commonly thought of as an immunogenic tumor, it is now clear that NSCLC is also capable of eliciting an endogenous immune response in patients with the disease and, in fact, has a natural history that may make NSCLC more amenable to vaccine therapy as an adjuvant treatment strategy. This review will high-light the major components of the immune system that may potentially interact with tumor-associated proteins as well as outline the immunologic similarities and differences between SCLC and NSCLC. Tumor antigens that elicit immune responses in patients with NSCLC will be discussed. Finally, clinical trials of whole-tumor cell vaccines, both autologous and allogeneic, and tumor antigen-specific vaccines will also be discussed.     

Immunotherapy in NSCLC patients with brain metastases. Understanding brain tumor microenvironment and dissecting outcomes from immune checkpoint blockade in the clinic

BackgroundBrain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC.MethodsWe reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models.ResultsAlthough limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8⁺ infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion.ConclusionsDiscordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases.     

肿瘤的精准免疫治疗

免疫检查点抑制剂和基因编辑 T 细胞通过靶向 T 细胞的调节通路增强抗肿瘤免疫,现已成为精准免疫治疗肿瘤的新武器。但免疫检查点抑制剂持续诱导免疫反应仅对少部分患者有效,而应用嵌合抗原受体或 T 细胞受体重新修饰 T 细胞的方法因缺乏肿瘤特异性抗原而受到限制。联合治疗模式和筛选优势人群是未来免疫检查点抑制剂发展的主要方向,设计双抗体或特异性抗体的 T 细胞可能提高精准免疫治疗的效果。     

非小细胞肺癌围手术期免疫治疗时代的麻醉思考

随着非小细胞肺癌（non-small cell lung cancer,NSCLC）围手术期免疫治疗时代的到来,胸外科的麻醉管理面临新的机会和挑战。不同麻醉方式和药物的选择会影响免疫功能和肿瘤生长转移,以免疫检查点抑制剂为代表的免疫治疗能够激活抗肿瘤免疫,影响局部和系统性免疫。麻醉和免疫治疗可能会产生不可预知的交互作用。本文将对麻醉方式和药物以及免疫治疗对NSCLC免疫状态和预后的影响进行综述,以期为NSCLC围手术期免疫治疗患者的麻醉管理提供新的思路。