PD-1/PD-L1免疫检查点抑制剂在晚期结直肠癌的药物治疗进展

结直肠癌是一种常见的恶性肿瘤,通过对肿瘤免疫逃逸机制的深入研究,程序性细胞凋亡蛋白1(PD-1)/程序性细胞凋亡蛋白配体1(PD-L1)免疫检查点抑制剂对晚期结直肠癌的治疗疗效不断得到各项临床试验的证实,其中pembrolizumab及nivolumab已成为NCCN指南推荐对于错配修复基因缺失/高频微卫星不稳定的晚期结直肠癌患者标准治疗失败后的二线或三线治疗.本文对近年来多项PD-1/PD-L1免疫检查点抑制剂单药治疗和联合治疗晚期结直肠癌的临床试验结果进行综述,并对可能预测抗PD-1/PD-L1抗体治疗效果的生物标志物相关研究进行文献复习.     

PD-1/PD-L1信号通路在结直肠癌免疫逃逸及其治疗中作用的研究进展

结直肠癌是常见的消化系统肿瘤。近年来,免疫治疗是继放化疗及靶向治疗之后,结直肠癌治疗领域的新方向。而作为T细胞免疫反应的协同刺激信号通路,程序性死亡分子1（programmed death-1,PD-1）/PD-1配体（PD-1 ligand,PD-L1)信号通路在肿瘤的免疫治疗中起着至关重要的作用。PD-1/PD-L1信号通路被激活后,可参与肿瘤的免疫逃逸,与肿瘤的发生、发展密切相关。体内外实验证实,阻断该通路可增强机体内源性抗肿瘤免疫效应。本文就PD-1/PD-L1信号通路及其阻滞剂在结直肠癌领域中的研究进展作一综述。     

PD-1/PD-L1在dMMR/MSI-H结直肠癌患者临床试验中的研究进展

结直肠癌是目前常见的肿瘤之一,关于DNA错配修复缺陷（dMMR）/微卫星高频不稳定（MSI-H）结直肠癌PD-1/PD-L1免疫疗法是目前关注的热点,多项临床试验已取得良好的疗效,2017年NCCN指南更新推荐纳武单抗(nivolumab)和派姆单抗(pembrolizumab)作为dMMR/MSI-H转移性结直肠癌二线或三线的药物选择。本文对当前dMMR/MSI-H结直肠癌特点、PD-1/PD-L1生物学功能、PD-1/PD-L1在结直肠癌中的治疗以及研究过程中出现的严重不良反应方面的研究进展作一综述。     

PD-1/PD-L1抑制剂在结直肠癌中的研究进展

在过去10余年,尽管晚期结直肠癌（colorectal cancer,CRC）的总生存率得到明显改善,但晚期CRC仍然是全球恶性肿瘤死亡的主要原因之一。化疗和生物治疗是目前主要治疗策略。PD-1抑制剂在错配修复缺陷型转移性CRC患者中取得的成功引起了研究者对CRC免疫治疗的关注。近年来,PD-1抑制剂在CRC中的疗效已成为研究热点。本文就CRC免疫分型和分子水平变化概况对免疫检查点抑制剂的新型联合治疗方案进行综述。      

免疫检查点PD-1/PD-L1阻断剂耐药机制的研究进展

免疫检查点蛋白通过复杂机制抑制抗肿瘤免疫,进而介导恶性肿瘤的“免疫逃逸”。2018年诺贝尔生理学或医学奖的两位得主发现了抑制上述机制的癌症疗法,为人类抗肿瘤治疗带来曙光。近年来,针对程序性死亡受体-1（PD-1）/程序性死亡受体配体-1（PD-L1）的免疫检查点阻断治疗在多种恶性肿瘤中取得较好疗效,将肿瘤免疫治疗推向新的里程碑。然而继之出现的耐药问题,限制了其临床应用,成为这一领域新的难题。本文就PD-1/PD-L1阻断剂耐药现象及相关机制作一综述。     

抗PD-1/PD-L1免疫检查点抑制剂的皮肤免疫相关不良反应的研究进展

随着免疫检查点抑制剂（immune checkpoint inhibitors,ICPI）在国内外临床试验和应用中的逐步推广,越来越多的患者从免疫治疗中获得显著的疗效。其中抗程序细胞死亡蛋白1（programmed death-1,PD-1）及其配体（PD-1 ligand,PD-L1）免疫检查点抑制剂已被美国食品药品管理局（FDA）批准用于恶性黑色素瘤、转移性鳞状非小细胞肺癌、晚期肾癌、头颈鳞状细胞癌、尿路上皮癌等肿瘤的治疗。但PD-1/PD-L1单抗也会引起免疫相关性皮肤、消化道、肝脏、内分泌、肺部等器官的不良反应,皮肤毒性如皮疹、白癜风、皮肤干燥症等是最常见也是最早发生的不良反应。     

PD-1/PD-L1抑制剂在骨肉瘤治疗中的研究进展

摘 要：骨肉瘤作为原发于骨细胞常见的恶性肿瘤,近几十年来疗效上没有本质上的提高。近年来PD-１/PD-L1抑制剂在多种恶性肿瘤中显现出了卓越的疗效,并在多个研究中显现出对骨肉瘤的抗肿瘤活性,有望进一步改善骨肉瘤,特别是转移及复发患者的治疗效果。全文综述总结近年PD-１/PD-L1抑制剂治疗骨肉瘤的主要进展。     

PD-1/PD-L1在肝细胞癌治疗中的研究进展

肝细胞癌（简称肝癌）起病隐匿,进展迅速,容易复发和转移。较长一段时间以来,传统的治疗手段难以进一步提高肝癌病人的预后,而免疫治疗被认为是最有希望解决这一难题的新型疗法。免疫检查点是肿瘤免疫逃逸的主要机制之一。其中,PD-1/PD-L1是抗肿瘤免疫治疗的重要靶点。近年来,基于PD-1/PD-L1信号通路的免疫疗法在实体肿瘤或血液系统恶性肿瘤中显示出令人振奋的抗癌作用。本文对PD-1/PD-L1在肝癌治疗中的相关研究进行综述,探讨PD-1/PD-L1阻断在肝癌治疗中的应用前景。     

免疫检查点抑制剂在结直肠癌中的研究进展CSCD

免疫治疗是当前实体肿瘤治疗研究的新方向,而在免疫系统中发挥负性调节分子的免疫检查点在限制抗肿瘤免疫反应中起着关键作用。针对PD-1及PD-L1、CTLA-4的免疫检查点抑制剂已被开发为抗肿瘤药物进行临床研究,dMMR/MSI-H型结直肠癌对免疫检查点抑制剂具有客观反应。本文基于结直肠癌免疫分型,对免疫检查点抑制剂在结直肠癌中的治疗方案进行综述。     

PD-1/PD-L1在结直肠癌中的研究进展

程序性死亡受体-1 (programmed death 1,PD-1)与其配体(programmed death-ligand l,PD-L1)是目前免疫治疗中关注的焦点.PD-1与其配体PD-L1结合导致肿瘤微环境中T细胞衰竭及免疫逃逸,阻断PD-1与PD-L1结合是有效的治疗靶点.针对阻断PD-1/PD-L1通路的单克隆抗体通过美国FDA的审批己应用于临床,并已证实在恶性黑色素瘤、肺癌、膀胱癌、胃癌、霍奇金淋巴瘤、乳腺癌等多种恶性肿瘤的治疗中取得了显著效果,目前该疗法在结直肠癌(colorectal cancer,CRC)的治疗研究中也显示出了良好的疗效.本文对当前PD-1/PD-L1的分子结构、肿瘤免疫中的生物学功能和在结直肠癌微环境中的特点、临床病理分子特点、PD-1/PD-L1抑制剂治疗与耐药及预后方面的研究进展作一综述.     

结直肠癌免疫检查点治疗的研究进展

目前免疫治疗正在非小细胞肺癌、黑色素瘤、膀胱癌等各个瘤种中如火如荼地开展,其治疗方法也多种多样,包括肿瘤疫苗治疗、过继性T细胞疗法、免疫检查点抑制剂治疗等,但目前结直肠癌免疫治疗主要集中于免疫检查点抑制剂(PD-1/PD-L1及CTLA-4抑制剂等).自从PD-1/PD-L1抑制剂在dMMR/MSI-H晚期结直肠癌患者...     

The Outlook for Immune Checkpoint Targeting Strategies in Colorectal Cancer

Encouraging clinical activity for checkpoint blockade in melanoma, lung cancer, and a growing list of other malignancies has supported enthusiasm for testing this strategy in colorectal cancer. Although frequent observations of T cell infiltration into colorectal cancer and a well-established list of target antigens suggest colorectal cancer should be amenable to this approach, there was limited clinical evidence until recent demonstration of substantial activity for anti-PD-1 antibody therapy in microsatellite instability high colorectal cancers. Addition of other therapeutic modalities such as targeted therapy, other checkpoint molecules, or other immunotherapies to anti-PD-1 antibodies is currently under evaluation with the hope that it will expand the possible spectrum of colorectal cancers treatable with checkpoint blockade.     

恶性肿瘤免疫检查点治疗的未来发展方向

2011年,FDA批准了第一个免疫检查点抑制剂（ICIs）——CTLA-4抑制剂Ipilimumab,以ICIs为代表的免疫检查点治疗（ICT）取得了突破进展。ICIs可诱导某些肿瘤患者亚群产生持久的抗肿瘤反应,但目前仍存在较多问题,比如获益人群的选择、严重免疫毒性的管理,以及如何通过合理的组合策略克服原发和适应性耐药机制来改善治疗反应等。本综述全面分析了当前对 ICIs 的反应和抵抗机制,并提出了通过更好的患者选择和合理组合来实现疗效最大化和毒性最小化的途径。     

Anti-PD-1/PD-L1 Therapy as a Promising Option for Non-Small Cell Lung Cancer: a Single arm Meta-Analysis

Anti-PD-1/PD-L1 antibodies showed satisfactory efficacy in treating non-small-cell lung cancer. We conducted this meta-analysis to explore the advantage subtypes and best therapeutic modalities of Anti-PD-1/PD-L1 therapy on NSCLC. A quantitative meta-analysis was performed through a systematic search in PubMed, Web of Science, and the Cochrane Library. The pooled ORR, 6-month progression-free survival rate (PFSR_6m), and 1-year overall survival rate (OSR_1y) were calculated and compared. 15 trials were included in this meta-analysis. Our analyses demonstrated the pooled ORR of 1st line and 2nd or more line anti-PD-1/PD-L1 therapy were 36.5 % (21.9–51.0 %) and 17.0 % (14.3–19.7 %), respectively. While the difference was significant (Z = 3.31, p < 0.001). The pooled ORR for non-squamous and squamous cell lung cancer were 18.5 % (16.0–21.1 %) and 17.9 % (14.4–21.5 %), respectively. The difference was not significant (Z = 0.27, p = 0.791). The pooled ORR for PD-L1 positive and negative patients were 29.6 % (21.6–37.6 %) and 13.5 % (10.6–16.3 %), respectively. The difference was significant (Z = 4.39, p < 0.001). The PFSR_6m for PD-L1 positive and negative NSCLC were 50.0 % (40.5–62.3 %) and 27.0 % (19.2–34.7 %). The difference was significant (Z = 3.72, p < 0.001). The OSR_1y for PD-L1 positive and negative NSCLC were 66.8 % (44.8 %-88.9 %) and 54.0 % (32.6–75.3 %). The difference was not significant (Z = 0.77, p = 0.441). Anti-PD-1/PD-L1 antibody can serve as a promising treatment option for NSCLC. Patients with positive PD-L1 expression may benefit more from anti-PD-1/PD-L1 therapy. 1st-line anti-PD-1/PD-L1 therapy can be chosen as the best modality. Squamous cell lung cancer also benefit from anti-PD-1/PD-L1 therapy.     

免疫检测点在宫颈癌中的研究进展

摘 要：T细胞是杀伤表达肿瘤特异性抗原的肿瘤细胞的重要成分。众所周知,肿瘤免疫逃逸是肿瘤发生发展的一个重要机制。免疫检测点治疗是以T细胞的调节通路为靶点来提高抗肿瘤效应的治疗方法。近年来,免疫检测点参与肿瘤免疫逃逸而受到极大的关注,并在肿瘤免疫治疗方面取得了有效进展。全文就免疫检测点与宫颈癌治疗的应用研究进展作一综述。     

The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment

Traditional treatment modalities for advanced cancer (radiotherapy, chemotherapy, or targeted agents) act directly on tumors to inhibit or destroy them. Along with surgery, these modalities are predominantly palliative, with toxicity and only modest improvements in survival in patients with advanced solid tumors. Accordingly, long-term survival rates for most patients with advanced cancer remain low, thus there is a need for cancer treatments with favorable benefit and toxicity profiles that can potentially result in long-term survival. The immune system plays a critical role in the recognition and eradication of tumor cells (“immune surveillance”), and immunotherapies based on this concept have been used for decades with some success against a few tumor types; however, most immunotherapies were limited by a lack of either substantial efficacy or specificity, resulting in toxicity. We now have a greater understanding of the complex interactions between the immune system and tumors and have identified key molecules that govern these interactions. This information has revitalized the interest in immunotherapy as an evolving treatment modality using immunotherapeutics designed to overcome the mechanisms exploited by tumors to evade immune destruction. Immunotherapies have potentially complementary mechanisms of action that may allow them to be combined with other immunotherapeutics, chemotherapy, targeted therapy, or other traditional therapies. This review discusses the concepts and data behind immunotherapies, with a focus on the checkpoint inhibitors and their responses, toxicities, and potential for long-term survival, and explores promising single-agent and combination therapies in development.

Implications for Practice:

Immunotherapy is an evolving treatment approach based on the role of the immune system in eradicating cancer. An example of an immunotherapeutic is ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) to augment antitumor immune responses. Ipilimumab is approved for advanced melanoma and induced long-term survival in a proportion of patients. The programmed death-1 (PD-1) checkpoint inhibitors are promising immunotherapies with demonstrated sustained antitumor responses in several tumors. Because they harness the patient’s own immune system, immunotherapies have the potential to be a powerful weapon against cancer.     

PD-1/PD-L1免疫检查点抑制剂致心脏毒性的研究进展

心脏毒性是抗肿瘤药物的严重不良反应,随着抗肿瘤药物的不断发展,免疫检查点抑制剂已被应用于多种癌症的治疗,特别是程序性死亡受体1(PD-1)或程序性死亡配体1(PD-L1)免疫检查点抑制剂近年来受到广泛关注,本文将从PD-1及PD-1/PD-L1免疫检查点抑制剂概述、PD-1/PD-L1免疫检查点抑制剂致心脏毒性的表现及...     

泌尿系统恶性肿瘤免疫检查点阻断治疗的进展

摘 要：在肿瘤微环境中,免疫检查点分子过表达会抑制肿瘤特异性T细胞的免疫活性,促进肿瘤的进展。靶向检查点的抗体通过阻断受体—配体相互作用,可以恢复T细胞的抗肿瘤免疫活性。对内分泌治疗抵抗的前列腺癌,CTLA-4抗体易普利姆玛（ipilimumab）单药的Ⅲ期试验中,总体结果为阴性。然而,在预后特征良好的亚组患者,可显著改善总体生存率。在2015~2016年,FDA批准纳武单抗（nivolumab）治疗抗血管治疗后的晚期RCC患者;阿特朱单抗（atezolizumab）治疗转移性尿路上皮癌患者。而且也报道了avelumab（PD-L1抑制剂）和派姆单抗（pembrolizumab）治疗泌尿系统癌症的数据。尽管存在一些差异,在转移性尿路上皮癌铂类治疗后,反应率均优于历史上的细胞毒化疗。此外,PD-L1高表达的肿瘤患者反应率接近30%,而且比化疗有更好的耐受性,3或4度毒性发生率小于15%。也有研究结果鼓励新的免疫疗法联合,与传统的抗癌药物联合治疗的临床试验。然而,也不是在每一个癌症患者都有反应。因此,根据免疫检查点阻断生物机制的科学认识,需要预计单药治疗和联合治疗的生物标志物,并提供早期治疗反应指标。