食管鳞癌免疫治疗临床研究新进展

摘 要：目前,针对食管鳞状细胞癌免疫治疗的多项临床研究正在进行。全文综述了免疫检查点抑制剂、过继性细胞免疫治疗、肿瘤疫苗等多种免疫治疗方法在食管鳞状细胞癌中的临床研究进展。目前免疫检查点抑制剂在食管鳞状细胞癌中取得了初步成效,肽段疫苗、过继性细胞免疫治疗也显示出治疗食管鳞状细胞癌的潜力,这些为改善晚期食管鳞状细胞癌患者生存带来新的希望。     

中晚期肝癌免疫治疗现状与前景

近年来,随着肿瘤免疫治疗的飞速发展及对肝癌免疫微环境认识的不断深入,以免疫检查点抑制剂为导向的新型系统治疗越来越受到关注。除此之外还有免疫治疗方法如肿瘤疫苗、溶瘤病毒、细胞因子等传统免疫方法也在肿瘤治疗中发挥着一定作用。而基于当前的多学科协作诊疗模式,肝癌的免疫治疗更多强调联合治疗,目前免疫联合治疗的方向主要有:双免疫检查点抑制剂联合、免疫检查点联合放化疗、免疫检查点联合抗血管生成药物等。对于肝癌的免疫治疗呈现了多方案的局面。因此,本文就肝癌免疫治疗的现状与前景进行综述,以期助于临床更好的应用。     

晚期肝癌一线治疗的研究进展

肝癌起病隐匿,进展迅速,大多数患者就诊时已失去根治性治疗机会,亟需系统药物治疗。近年来,靶向治疗和免疫治疗迅速发展,使晚期肝癌的一线治疗有了更多的选择。靶向治疗药物包括索拉非尼、仑伐替尼、多纳非尼等,而免疫治疗包括免疫单药治疗和免疫联合治疗。以免疫检查点抑制剂为核心的治疗策略为肝癌患者带来了新的希望,特别是免疫检查点抑制剂联合抗血管生成药物一线治疗肝癌的成功,开启了肝癌的免疫联合治疗模式。在过去20年,晚期肝癌的全身治疗格局发生了重大变化,随着系统治疗方案的增加,合理的治疗顺序及一线治疗的选择对改善患者的预后至关重要。本文就晚期肝癌一线治疗的临床研究进展进行综述。     

免疫检查点抑制剂治疗原发性肝癌生物标志物的研究进展

免疫检查点抑制剂已成为原发性肝癌的一种有前景的治疗策略。但是,持久的反应和良好的长期疗效也仅限于一小部分患者。寻找有效的生物标志物来预测免疫检查点抑制剂治疗原发性肝癌的疗效有重要的指导价值。该文将概述生物标志物在原发性肝癌免疫治疗中的最新研究进展。     

非酒精性脂肪肝对免疫检查点抑制剂治疗肝细胞癌疗效的影响及机制研究进展

近年来,非酒精性脂肪肝合并肝细胞癌的患者数量逐渐上升,免疫治疗在晚期肝细胞癌的治疗中扮演着越来越重要的角色。既往研究发现非酒精性脂肪肝可以影响肝细胞癌免疫治疗的疗效,但机制不清,可能与这些因素相关：非酒精性脂肪肝中CD8⁺PD-1⁺T细胞增多导致肝脏细胞增殖能力缺陷;锌指蛋白64激活CSF1抑制抗肿瘤免疫;PCSK9下调LDLR水平抑制肿瘤微环境中CD8⁺T细胞免疫应答;免疫应答的缺失导致肝损伤等。研究发现联合使用仑伐替尼、PKCa抑制剂、PCSK9蛋白的抑制、铁死亡诱导剂、HIF2a小分子抑制剂可以改善非酒精性脂肪肝相关肝细胞癌免疫检查点抑制剂的疗效。本文就非酒精性脂肪肝对肝脏免疫微环境和肝细胞癌免疫检查点抑制剂疗效的影响和机制,以及如何改善非酒精性脂肪肝相关肝细胞癌免疫检查点抑制剂疗效的研究进行综述。     

肝细胞癌的免疫治疗研究进展

肝细胞肝癌（hepatocellular carcinoma，HCC）约占原发肝癌的75%~85%，是全球发病率较高的恶性肿瘤之一，免疫治疗目前被认为是较有前景的防治肝癌术后复发及病情进展的治疗手段。肝癌免疫治疗方案主要分为主动和被动免疫治疗，包括肿瘤疫苗、免疫检查点抑制剂和过继性免疫细胞输注治疗等。本文就近年肝癌免疫治疗的现状和研究进展进行概述。      

靶向联合免疫治疗在不可切除肝细胞癌的临床研究进展

原发性肝癌是国内发病率及死亡率都位居前列的恶性肿瘤,约70%的肝癌患者确诊时已经是中晚期,失去根治性手术机会。晚期肝癌的治疗一直是困扰临床医生的一大难题,2008年国内批准索拉非尼作为晚期肝癌一线治疗的靶向药物,开启靶向治疗时代,然而疗效不尽人意,患者的中位生存期仅延长了近3个月,客观缓解率仅为2%。近年来,随着免疫检查点抑制剂的快速发展,晚期肝癌治疗迎来免疫新纪元。2019年美国临床肿瘤协会上公布了IMbrave150研究,探索阿替利珠单抗联合贝伐珠单抗对比索拉非尼在晚期肝癌一线治疗的疗效,发现中位生存期延长近6个月,且亚组分析发现中国人群中位生存期达到24个月,延长近13个月。2020年阿替利珠单抗联合贝伐珠单抗被国内外各大指南列为一线推荐。IMbrave150研究拉开了靶向联合免疫治疗的序幕,同时也推动国内外多项临床研究,开启靶向联合免疫治疗在不可切除肝细胞癌探索的新征程。本文旨在探讨靶向联合免疫治疗在不可切除肝细胞癌中的应用范围、不良反应、发展趋势及挑战。     

放疗联合免疫检查点抑制剂在食管癌中的应用

摘 要：近年来以免疫检查点抑制剂为代表的免疫治疗作为一种新兴的治疗方法，使食管癌的治疗步入了新的阶段。既往研究表明免疫治疗可以提高晚期转移性食管癌患者的生存率，且免疫检查点抑制剂与放射治疗相结合可更好地发挥局部治疗作用，放疗联合免疫检查点抑制剂应用于围手术期、局部晚期和晚期食管癌的各项临床研究取得了可观的成效。全文对近年来放疗联合免疫检查点抑制剂在食管癌中的应用进行综述。     

复发转移性头颈鳞状细胞癌免疫治疗现状和探索

目的 世界范围内,头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)发病率在恶性肿瘤中居第7位,复发转移性(recurrent or metastatic,R/M) HNSCC生活质量下降,治疗方法少,预后差.近年来,以免疫检查点抑制剂为代表的免疫治疗取得突破性进展,成为黑色素瘤、肺癌等多种肿瘤有效的治疗选择.本研究对R/M HNSCC免疫治疗的现状和进展作一综述.方法 以“头颈鳞癌,免疫治疗,免疫检查点抑制剂,过继T细胞治疗,肿瘤疫苗”等为关键词,应用PubMed和CNKI期刊全文数据库检索系统以及ClinicalTrials.gov网站,检索2001-01-2017-01的相关文献及注册临床研究,共检索到英文文献138篇,中文文献84篇.纳入标准:(1)R/M HNSCC;(2)免疫治疗现状及进展;(3)免疫治疗相关临床研究.共纳入38篇文献进行分析.结果 R/M HNSCC中免疫治疗研究广泛开展并逐渐深入,尤其是免疫检查点抑制剂.程序性细胞死亡1(programmed cell death-1,PDq)抑制剂(Pembrolizumab和Nivolumab)显示出明显疗效,因此被食品药品管理局(food and drug administration,FDA)批准用于R/M HNSCC的治疗.尽管其他免疫检查点抑制剂如程序性死亡配体1(programmed death ligand-1,PD-L1)抑制剂(Durvalumab和Avelumab)和细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抑制剂(Ipilimumab和Tremelimumab)尚无Ⅲ期临床研究结果发表来证明其确切疗效,但有一系列临床研究正在进行中.过继T细胞治疗和肿瘤疫苗的免疫治疗模式也在探索中.此外,在R/M HNSCC免疫治疗中根据生物标志物筛选有效患者,联合治疗提高疗效以及不良反应的监测及治疗等方面也被关注.结论 R/M HNSCC中免疫治疗有良好前景,但也存在许多挑战,如何筛选免疫治疗最有效的人群、探索免疫治疗模式及提高疗效仍是未来研究重点.     

原发性肝癌中PD-L1表达的调控机制

免疫疗法的应用是目前肿瘤研究的热点,尤其是免疫检查点抑制剂在晚期不可手术切除原发性肝癌的治疗中发挥了重要的作用。但不同患者免疫检查点抑制剂治疗疗效的差异较大,这引起了行业对PD-L1在肝脏肿瘤免疫逃逸中的调节机制的关注。PD-L1在肝癌中是由多个层次和多个信号通路调控的,包括表观遗传、转录调控、转录后调控和翻译后修饰。有研究发现PD-L1的高表达可能是影响原发性肝癌免疫治疗的主要因素,因此明确原发性肝癌中PD-L1的调控机制,可为原发性肝癌免疫治疗以及免疫联合治疗策略提供更多的依据。     

Immune checkpoint inhibitors for hepatocellular carcinoma

The position of immunotherapy as a pillar of systemic cancer treatment has been firmly established over the past decade. Immune checkpoint inhibitors are a welcome option for patients with different malignancies. This is in part because they offer the possibility of durable benefit, even for patients who have failed other treatment modalities. The recent demonstration that immunotherapy is effective for patients with hepatocellular carcinoma (HCC) is a milestone in the history of this recalcitrant disease. The treatment of HCC has been a challenge, and for many years was limited to the tyrosine kinase inhibitor sorafenib and to several novel tyrosine kinase inhibitors that have shown efficacy and have been approved. The current role of immune checkpoint inhibitors in the management of HCC, and how this role is likely to evolve in the years ahead, are key. Other than efforts evaluating single checkpoint inhibitors, potential combination strategies, including combinations with existing local and systemic approaches, including novel therapies are evolving. This is understandably of special interest considering the potential unique immune system of the liver, which may impact the use of immunotherapy in patients with HCC going forward, and how can it be enhanced further.     

Immune checkpoint inhibitors in hepatocellular carcinoma: A review of current clinical trials

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a poor prognosis due to advanced disease presentation or recurrence despite curative-intent resection. Since the approval of sorafenib in 2007, few systemic therapies offered a significant improvement in treatment outcomes. Over the last 3 years, however, rapid advancements in the field of immunotherapy have led to approval of checkpoint inhibitors in 2020 for use in advanced HCC. Since then, a few other clinical trials have shown promising results in the adjuvant and neoadjuvant setting. The objective of this review is to summarize data from existing clinical trials evaluating the use of systemic immune checkpoint inhibitors in HCC and to follow the natural evolution of this development across the metastatic, adjuvant, and neoadjuvant landscapes.     

Interventional therapy combined with immune checkpoint inhibitors: Emerging opportunities for cancer treatment in the era of immunotherapy

Immune checkpoint inhibitors-based immunotherapy offers a new effective modality in the treatment of advanced malignancies. Considering the remarkable efficacy of immune checkpoint inhibitors in clinical trials, the FDA has approved a variety of immune checkpoint inhibitors for the treatment of advanced tumors. However, only limited patients with certain cancers can benefit from monotherapy of immune checkpoint inhibitors. Interventional therapy for cancer can not only destroy the primary tumors, but also regulate the immune system through different mechanisms, which provides a potential possibility for the combination of immune checkpoint inhibitors and interventional modalities in cancer treatment. This article reviews the possible synergistic mechanisms of interventional therapy combined with immune checkpoint inhibitors and summarizes the research progress of the combined therapy in cancer treatment.     

免疫检查点抑制剂治疗结直肠癌的疗效及肠道菌群对其疗效影响的研究进展

随着免疫治疗领域的快速发展,越来越多的免疫检查点抑制剂被应用于临床。免疫治疗为结直肠癌晚期转移患者提供了一种新的治疗选择。研究证实,错配修复缺陷/高度微卫星不稳定（dMMR/MSI-H）状态的晚期转移性结直肠癌患者对免疫治疗更敏感,有较为客观及持续的临床反应。在肿瘤免疫治疗的应答中,肠道菌群被证实有一定的调节作用,部分细菌可通过免疫系统或机体代谢功能来影响免疫检查点抑制剂的疗效。随着研究的进展,肠道菌群不仅有望成为结直肠癌免疫治疗的疗效预测性生物标志物,也可能成为影响结直肠癌免疫治疗结果的关键调控因素,在今后的临床治疗中,为更多的晚期结直肠癌患者使用免疫检查点抑制剂获益带来可能性。     

Liver immunotolerance and hepatocellular carcinoma: Patho-physiological mechanisms and therapeutic perspectives

At the moment of the diagnosis of hepatocellular carcinoma (HCC), 70% of patients have only access to palliative treatments, with very few therapeutic options. Liver immunology is very specific, and liver immunotolerance is particularly developed because of the constant and massive influx of antigens. Deregulation of hepatic immunotolerance is implicated in chronic liver diseases development and particularly in liver carcinogenesis. For these reasons, HCC may be an excellent candidate for anticancer immunotherapies such as immune checkpoint inhibitors targeting CTLA-4 and PD-L1/PD-1. Nonetheless, because of the specific immune environment of the liver and the frequent association of HCC with hepatocellular insufficiency, the safety and the efficacy of these new treatments have to be properly studied in this situation. Thus, multiple phase II and III studies are in progress studying immune checkpoint inhibitor monotherapies, combination of different immunotherapies or local strategies such as transarterial chemoembolization combined with immune checkpoint inhibitors. Currently, only the final results of the tremelimumab phase II and the Nivolumab phase I/II study (CheckMate-040) are available. The latter is promising but need to be confirmed by the ongoing phase III studies to confirm the place of immunotherapy in the treatment of HCC. With many new molecular targets and therapeutic combination, immunotherapy represents a new hope in treating HCC patients although serious evaluation is still needed to confirm its interest.     

PD-1/PD-L1抑制剂治疗晚期肝细胞癌的机制及研究进展

原发性肝癌起病隐匿,恶性程度高,易发生进展及转移,往往发现疾病时已是肝癌中晚期。较长一段时间内,对于肝癌的主要治疗手段包括手术、放化疗、介入治疗及靶向治疗。但传统治疗方法疗效有限,近年来,随着对原发性肝癌的免疫系统研究逐步深入,免疫治疗已然成为一种新兴的治疗手段,其中以程序性死亡蛋白-1（PD-1）/程序性死亡蛋白配体-1（PD-L1）为靶点的免疫疗法在非小细胞肺癌及肾细胞癌的临床应用中取得了明显疗效。因此,许多研究者开始进一步探索PD-1/PD-L1抑制剂在肝癌中的治疗效果。本文将对PD-1/PD-L1抑制剂治疗肝癌的机制及现阶段国内外多项免疫治疗取得的成效作一综述。