晚期非小细胞肺癌免疫治疗现状及未来方向

肺癌仍然是中国发病率和死亡率最高的恶性肿瘤,其中非小细胞肺癌（non-small cell lung cancer,NSCLC）约占80%以上。以靶向程序性死亡[蛋白]-1（programmed death protein-1,PD-1）或程序性死亡[蛋白]配体-1（programmed death ligand-1,PD-L1）的免疫检查点抑制剂（immune checkpoint inhibitor,ICI）为基础的治疗已成为了晚期肺癌的标准治疗手段之一。本综述将对晚期NSCLC免疫治疗的现状予以梳理,探讨现阶段面临的问题与挑战,并思考与展望未来发展方向。     

晚期非小细胞肺癌化疗联合免疫治疗进展

化疗在晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）的治疗中发挥着重要的作用，但近年来免疫检查点抑制剂在晚期NSCLC的治疗中也表现出了良好的效果，因此两者联合治疗能否产生更佳的治疗效果成为了人们关注的焦点。本文综述总结了程序性死亡受体1（programmed death 1，PD-1/PD-L1）抑制剂、细胞毒性T淋巴细胞相关蛋白（cytotoxic T-lymphocyte-associat? ed protein 4，CTLA4）抑制剂等不同免疫治疗方案分别联合不同化疗方案治疗晚期NSCLC的疗效及安全性，并阐述联合治疗方案疗效增加可能的机制，同时对晚期NSCLC未来的治疗模式做出了展望。      

PD-1/PD-L1在非小细胞肺癌中的临床研究进展

近年来,免疫治疗在癌症研究中取得了突飞猛进的发展。以程序性死亡受体-1（programmed cell death-1,PD-1）及其配体程序性死亡配体-1（programmed cell death-ligand 1,PD-L1）为靶点的免疫治疗药物在非小细胞肺癌（non-small cell lung cancer,NSCLC）的治疗中显示出了良好的疗效和耐受性,治疗前景值得期待。本文对PD-1/PD-L1治疗NSCLC的临床研究现状进行综述。      

病理学指导下的非小细胞肺癌个体化免疫治疗

在肺癌个体化免疫治疗时代，如何有效地筛选程序性死亡［蛋白］-1（programmed death-1，PD-1）/程序性死亡［蛋白］配体-1（programmed death ligand-1，PD-L1）免疫检查点抑制剂潜在获益人群成为免疫治疗时代面临的新挑战。病理科医师通过免疫组织化学检测非小细胞肺癌（non-small cell lung cancer，NSCLC）组织中PD-L1的表达水平，可为预测PD-1/PD-L1免疫检查点抑制剂治疗晚期NSCLC的疗效和预后提供准确可靠的依据。此外，病理科医师可通过传统病理学方法观察主要病理学缓解（major pathological response，MPR）程度，进一步评价早中期肺癌免疫新辅助治疗的效果。对目前病理学诊断指导下的NSCLC个体化免疫治疗的进展以及未来的发展方向进行综述。     

免疫治疗联合放疗治疗晚期非小细胞肺癌的进展

晚期非小细胞肺癌（non-small cell lung cancer，NSCLC）患者手术、放疗、化疗治疗效果欠佳，预后较差。近年来针对NSCLC免疫治疗联合放疗的研究越来越多，可取得较好的肿瘤控制效果。本文就NSCLC免疫治疗联合放射治疗的相关进展进行综述。     

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。     

放疗联合免疫检查点抑制剂在晚期非小细胞肺癌中的研究进展

非小细胞肺癌（Non-small cell lung cancer，NSCLC）占肺癌总数的85%左右，且多数确诊时疾病已出现进展或转移，放射治疗是主要的治疗手段之一；免疫检查点抑制剂（immune checkpoint inhibitors，ICIs）是免疫治疗中最常见的一种，已逐渐成为晚期NSCLC综合治疗的重要组成部分。近年研究发现，放疗在抗肿瘤免疫调节中发挥重要的作用，可提高免疫治疗疗效和敏感性，而免疫治疗可增强放疗的免疫效应，从而增强抗肿瘤效果（即放疗和免疫治疗具有协同作用），开辟了肿瘤治疗的新时代：免疫-放射治疗。然而，在晚期NSCLC中，放疗和ICIs联合的有效性和安全性尚无定论，二者联合作用时放疗剂量、放疗分割方式、联合治疗的时机和治疗疗效的预测因子等仍有争议。本文通过对两种治疗方式联合的分类、影响因素和临床应用等方面进行综述，以期为寻找非小细胞肺癌的最佳治疗策略提供参考。     

广泛期小细胞肺癌放射治疗进展

广泛期小细胞肺癌（extensive-stage small cell lung cancer，ES-SCLC）约占小细胞肺癌（（small cell lung cancer，SCLC）的2/3，治疗以化疗为主，辅以放疗等综合治疗。虽然SCLC对放化疗反应敏感、初治缓解率高，但几乎所有ES-SCLC都会发生复发及进展，迫切需要新的治疗策略以提高疗效。近年来，放疗在ES-SCLC中进展主要包括脑预防照射（prophylactic cranial irradiation，PCI）和胸部放疗（thoracic radiotherapy，TRT）。此外，免疫检查点抑制剂展现了良好的抗肿瘤活性，有望成为该领域治疗的重要突破口。本文将对ES-SCLC在放疗和免疫治疗以及其他治疗的临床研究进展方面进行综述。      

小细胞肺癌免疫治疗相关生物标志物研究进展

最近30年来小细胞肺癌（small cell lung cancer,SCLC）的治疗手段无明显突破,整体预后也无显著改善。随着免疫治疗时代的开启,免疫检查点抑制剂在SCLC治疗中取得了重大进展,但整体获益仍有限。如何筛选获益人群以进一步提高免疫治疗效果是当下SCLC研究的热点问题之一。通过概述SCLC现状,聚焦SCLC免疫治疗相关生物标志物,综述近年来SCLC免疫治疗标志物研究现状与进展,以期为未来优化免疫治疗策略提供线索和思路。     

PD-1/PD-L1治疗非小细胞肺癌的研究进展

程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡配体-1（programmed cell death-ligand 1,PD-L1）信号通路与肿瘤免疫逃逸密切相关,针对PD-1/PD-L1通路的免疫检查点抑制剂为非小细胞肺癌（non-small cell lung cancer,NSCLC）患者提供了一种新的治疗选择,并且显示出良好的疗效和安全性。本文对PD-1/PD-L1抑制剂治疗NSCLC的临床研究进展进行综述。      

多色标记免疫组织化学染色和免疫荧光染色在肺癌免疫治疗中的研究进展

肺癌是目前临床上最常见的恶性肿瘤,严重威胁着患者的生命健康及生活质量。程序性细胞死亡受体1(programmed cell death receptor 1, PD-1)及其配体(programmed cell death ligand 1, PD-L1)抑制剂为非小细胞肺癌(non-small cell lung cancer, NSCLC)患者提供了新的治疗策略。现有的生物标志物检测对准确选择免疫治疗受益的患者均有一定的价值,但都存在着局限性。多标记免疫组织化学/免疫荧光(multiplex immunohistochemistry/immunofluorescence,mIHC/IF)技术允许在单一组织切片上同时检测多个抗体,并对细胞组成、细胞功能和细胞-细胞相互作用进行全面研究。国内外已有大量研究使用mIHC/IF技术对肿瘤免疫微环境(tumor immune microenvironment, TIME)下特异性免疫细胞群进行了探索,发现其有助于肺癌患者临床预后判断及疗效预测。肺癌免疫治疗时代,这项技术在转化研究和临床实践中均具有良好的应用前景。本文就mIHC/IF检测方法在肺癌免疫治疗中的研究进展进行了总结和展望。     

非小细胞肺癌免疫治疗研究进展

近年来,肺癌的治疗手段层出不穷,从传统化疗到靶向药物,再到免疫检查点抑制剂的出现,很大程度上改善了患者的预后,延长了患者生存期。免疫检查点抑制剂的应用,即免疫治疗,一改传统的治疗方式,作用于程序性细胞死亡蛋白-1（PD-1）及其配体（PD-L1）发挥有效且持久的抗肿瘤反应。本文主要介绍了近年来免疫治疗一线、二线应用于非小细胞肺癌（NSCLC）的研究情况,影响免疫治疗疗效的因素,及免疫治疗的相关毒副反应。     

纳武利尤单抗在非小细胞肺癌治疗中的研究进展

肺癌是全球癌症死亡的主要原因之一。其中非小细胞肺癌(non-small cell lung cancer,NSCLC)占所有肺癌病例的85%以上,尽管化疗及靶向治疗改善了患者临床疗效,但预后仍欠佳。免疫治疗的发展改变了NSCLC患者的治疗策略。纳武利尤单抗是一种针对程序性死亡受体-1(programmed cell death-1,PD-1)的完全人源化的IgG4单克隆抗体,是首个被批准用于晚期NSCLC治疗的免疫检查点抑制剂。纳武利尤单抗已经成为晚期NSCLC治疗的主要药物,但临床上尚缺乏预测疗效的生物标志物。本文针对纳武利尤单抗的作用机制、药代动力学、单药治疗、联合治疗、不良反应和潜在生物标志物的最新进展进行综述。     

PD-1及PD-L1抑制剂在前列腺癌治疗中的研究现状

前列腺癌是男性常见的恶性肿瘤,目前主要的治疗手段是根治性前列腺切除术(RP)以及雄激素剥夺疗法(ADT),但两者均有其各自的局限性。近年来免疫治疗发展迅速,其中细胞程序性死亡受体-1(PD-1)及细胞程序性死亡配体-1(PD-L1)作为免疫治疗的理想靶点,其抑制剂在治疗肺癌、结肠癌等多种癌症中发挥了越来越重要的作用。而随着PD-1/PD-L1在前列腺癌方面的研究进展及深入,其在前列腺癌中的作用机制也逐渐明了,PD-1/PD-L1抑制剂在前列腺癌治疗上也将具有广阔的前景。本文将就PD-1及PD-L1在前列腺癌中的表达、作用机制及其抑制剂治疗前列腺癌的相关研究进展作一综述。     

免疫抑制剂PD-1/PD-L1治疗卵巢癌的研究进展

卵巢癌是欧洲和美国女性中最致命的妇科恶性肿瘤,发病机制复杂、易复发,给予积极治疗预后仍较差。目前免疫疗法成为继传统疗法后又一新型抗肿瘤疗法,其中程序性细胞死亡受体-1(PD-1)/程序性细胞死亡配体-1(PD-L1)抑制剂在包括黑色素瘤、非小细胞肺癌等在内的多种恶性肿瘤治疗中取得显著疗效,但其在卵巢癌的临床治疗中的效果有待研究。本文就PD-1/PD-L1免疫抑制剂在卵巢癌的治疗进展及副反应处理方面进行综述,探讨免疫抑制剂应用于卵巢癌的可行性。     

Biomarkers of Immune Checkpoint Inhibitors in Non–Small Cell Lung Cancer: Beyond PD-L1

Immunotherapy has markedly improved the survival rate of patients with non–small cell lung cancer (NSCLC) and has introduced a new era in lung cancer treatment. Although some patients achieve durable responses to checkpoint blockade, not all experience such benefits, and some suffer from significant immunotoxicities. Thus, it is crucial to identify potential biomarkers suitable for screening the population that may benefit from immunotherapy. Based on the current clinical trials, the aim of the present study was to review the biomarkers for immune checkpoint inhibition that may have the potential to predict the response to immunotherapy in patients with lung cancer. A non-systematic literature review was done. We searched for eligible randomized controlled trials (RCTs) from PubMed, Embase, and the Cochrane Central Register of Controlled Trials from January 2015 to January 2021. The keywords included biomarkers, immunotherapy, immune checkpoint inhibition, programmed death ligand 1 (PD-L1), and non–small cell lung cancer. Additional biomarkers beyond PD-L1 that have been shown to have predictive capacity include tumor mutational burden, microsatellite instability, lung immune prognostic index, gut microbiome, and certain alterations in genes (eg, STK11 deletion, LKB1 kinase mutation, MDM2/4 amplification) that confer immunoresistance. The biomarkers reviewed in this article could help us better select the appropriate immunotherapy treatment for patients with NSCLC.     

Immunotherapy in the First-Line Setting in Wild-Type NSCLC

Treatment algorithms in the treatment of advanced non-small cell lung cancer (NSCLC) continue to evolve as new therapeutics show positive efficacy improvements. This review article summarizes the data for the use of immunotherapy for treatment in first-line stage IV NSCLC, organized by the following four sections: single-agent immunotherapy, immunotherapy and chemotherapy, dual immunotherapy, and dual immunotherapy and chemotherapy. The results are summarized and tabulated. Finally, application of the trial data is illustrated in four clinical scenarios depending on the programmed death-ligand 1 (PD-L1) expression levels. Single checkpoint inhibitors have become an easy and excellent treatment in patients whose tumors have high PD-L1 expression. Adding chemotherapy to immunotherapy benefits our patients. Immunotherapy, with or without chemotherapy, is now the standard of care in the first-line setting in patients without EGFR, ALK, or ROS driver mutations.     

Immunotherapy Comes of Age in Lung Cancer

Lung carcinoma is the leading cause of death by cancer worldwide. When possible, surgery is the best treatment strategy for patients with non–small-cell lung cancer. However, even with curative-intent therapy, most patients will develop local or systemic recurrence and, ultimately, succumb to their disease. In recent years, evidence on the role of the antitumor activity of the immune system and the understanding of tumor immunosurveillance have resulted in the emergence of immunotherapy as a promising therapeutic approach in lung cancer. The main approaches are immune checkpoint inhibition, such as blockade of the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 receptors and the programmed cell death-1 ligand, and vaccine therapy, which elicits specific antitumor immunity against relevant tumor-associated antigens. We have reviewed recently reported results from clinical trials and the possible future role of vaccine therapy and immune checkpoint inhibition in the treatment of small cell lung cancer and non–small-cell lung cancer.     

The Significance of the PD-L1 Expression in Non–Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers

Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non–small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors.