免疫检查点PD-1/PD-L1抑制剂的研究概况

免疫检查点抑制剂里程碑式的成功推动了肿瘤免疫成为化疗、放疗、靶向治疗及手术之后又一有效的癌症治疗手段。目前上市的免疫检查点抑制剂包括靶向于细胞毒T淋巴细胞相关蛋白4（Cytotoxic T lymphocyte-associated antigen-4,CTLA-4）的伊匹木单抗、靶向于程序性细胞死亡蛋白1（Programmed death 1,PD-1）的纳武单抗及靶向于程序性细胞死亡蛋白配体1（Programmed death-ligand 1,PD-L1）的阿特珠单抗等。大分子药物因其较长的半衰期而能降低治疗频率,但较差的药动学表现及昂贵的生产成本限制了其发展及应用。生物利用度良好且价格相对低廉的小分子免疫检查点抑制剂亟待开发。PD-1及配体PD-L1因其在T细胞失能过程中的重要作用成为备受关注的免疫检查点。2016年,Curis/Aurigene公司开发了全球首个口服PD-1/PD-L1小分子抑制剂CA-170并获批一期临床。使得越来越多研究者着手这一领域小分子抑制剂的开发。本文以免疫检查点PD-1/PD-L1为例,从其生物学背景出发,介绍该靶点小分子抑制剂的研发现状并分析可能存在的技术瓶颈,为后续更为深入的研究奠定基础。     

免疫检查点及PD-1/PD-L1抑制药在肿瘤免疫诊断治疗中的应用

程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)单克隆抗体为代表的免疫检查点抑制药在肿瘤治疗领域取得了巨大的成功。故对免疫检查点抑制药在肿瘤免疫中的作用进行概述,并分析了免疫检查点抑制药的研究热点PD-1/PD-L1通路在抗肿瘤免疫的治疗意义,再对目前PD-1/PD-L1抑制药在诊断、治疗和预后中的应用调查,在此基础上分析PD-1/PD-L1抑制药进一步应用需要研究的问题,以期为PD-1/PD-L1抑制药进一步应用提供研究参考。     

抗PD-1/PD-L1单抗在肿瘤治疗中耐药机制研究进展

抗程序性死亡受体/配体1 (PD-1/PD-L1)单抗因其在多种恶性肿瘤中临床疗效良好且患者能获得长期缓解,被认为是有潜力的抗肿瘤药物,但其高发的耐药问题(包括原发性及获得性耐药)仍不容忽视。目前研究显示抗PD-1/PD-L1单抗的原发性耐药与肿瘤免疫微环境动态变化、肿瘤突变负荷及致癌通路激活等因素相关。获得性耐药机制包括新抗原谱系演化,JAK1/JAK2、β2-微球蛋白基因突变及衰竭T细胞表观遗传学稳定性。因此,可通过联合放化疗增强肿瘤免疫原性,通过阻断共表达的抑制性受体、细胞因子等打破肿瘤微环境免疫抑制状态,提高抗PD-1/PD-L1单抗的临床疗效。     

PD-1/PD-L1抑制剂介导的1型糖尿病研究进展

近年来,免疫检查点抑制剂已成为晚期癌症的重要治疗方法之一,随着免疫检查点抑制剂应用于临床,免疫相关不良反应也随之增多。其中,免疫相关的血糖异常越来越被关注,尤以1型糖尿病(T1DM)危害最大。本文主要综述程序性细胞死亡受体1/程序性细胞死亡-配体(Programmed cell death 1/Programmed cell death 1 ligand 1,PD-1/PD-L1)抑制剂治疗引起的1型糖尿病的临床特征、发病机制以及诊疗策略等,为肿瘤免疫的安全用药提供参考。     

基于PD-1/PD-L1通路探讨补肾解毒散结方对晚期结直肠癌患者免疫微环境的影响

目的 分析基于细胞程序性死亡受体1(Programmed death receptor-1,PD-1)/细胞程序性死亡受体-配体1(Programmed death receptor ligand-1,PD-L1)通路探讨补肾解毒散结方对晚期结直肠癌患者免疫微环境的影响。方法 选择2020年1月-2021年12月上海中医药大学附属曙光医院胃肠外科收治的50例晚期结直肠癌患者,按照随机数字表法分为研究组和对照组。对照组(n=25)采用mFOLFOX6化疗+PD-1抑制剂,研究组(n=25)在此基础上给予补肾解毒散结方,服用2周。分别于治疗前、治疗后(化疗4个周期),采用流式细胞仪检测T淋巴细胞亚群,酶联免疫吸附法检测血清PD-1、PD-L1水平,分析其表达与临床疗效及免疫微环境的关系。结果 研究组的疾病控制率(Disease control rate, DCR)为64.0%,明显高于对照组36.0%(P<0.05);治疗后,研究组CD3⁺、CD4⁺水平明显升高(P<0.05),CD8⁺、CD4⁺     

抗菌药物对PD-1/PD-L1抗体免疫治疗有效性影响的研究

目的 为恶性肿瘤患者在使用免疫检查点抑制剂(Immune checkpoint inhibitors,ICI)期间,合理选用临床抗菌药物方案及改善ICI治疗临床结局策略上提供参考.方法 检索CNKI、万方、PubMed、Web of Science等数据库的国内外文献,对使用免疫检查点抑制剂期间使用抗菌药物的临床研究,...     

PD-1/PD-L1免疫检查点抑制剂治疗三阴性乳腺癌的研究进展

三阴性乳腺癌(TNBC)是一种具有特殊生物学行为及临床病理特征的乳腺癌亚型.具有高度的肿瘤异质性,进展迅速、侵袭转移能力强、预后差,死亡率高等特点.遗传多样性及药物耐受性差,内分泌及抗Her-2治疗均无效,目前临床尚缺乏特效治疗手段,亦是临床诊疗上的难点.肿瘤免疫疗法是采用各种手段激活身体内的抗肿瘤免疫反应,最后杀死、...     

PD-1/PD-L1抑制剂在肝癌免疫治疗中的研究进展

原发性肝癌是目前我国第4位常见恶性肿瘤,其恶性程度极高,传统治疗方法对晚期肝癌的治疗效果欠佳。随着肿瘤免疫治疗机制的进一步阐明,许多免疫检查点抑制剂类新药被研发,并广泛地用于临床治疗中,成为继手术、放疗、化疗和中医药特色诊疗后治疗恶性肿瘤的新模式。细胞毒性T淋巴细胞相关抗原4 (CTLA-4)、程序性细胞死亡蛋白-1 (PD-1)和程序性细胞死亡配体1 (PD-L1)等免疫检查点是肿瘤免疫治疗的主要靶点。临床研究表明,PD-1/PD-L1抑制剂能使更多的肝癌患者获益,包括肝细胞肝癌(HCC)和胆管癌(ICC)2种主要的原发性肝癌。本文主要对以PD-1/PD-L1(程序性细胞死亡受体-1/程序性细胞死亡配体1)为靶点的肝癌免疫治疗中的研究进展进行综述。     

肿瘤免疫检查点治疗及其药物递送策略

肿瘤免疫检查点治疗是基于抑制消极免疫调节机制新原理而发展起来的临床治疗策略。本文对肿瘤免疫检查点治疗及其药物递送策略进行了综述和评述,主要包括免疫力与肿瘤治疗、免疫检查点治疗及其作用机制、免疫检查点治疗的临床应用及其药物、程序性死亡受体1 (programmed cell death protein 1, PD1)/细胞程序性死亡受体配体1 (programmed cell death 1 ligand 1, PDL1)治疗免疫耐药性与对策、免疫检查点治疗药物的递送策略等若干方面。肿瘤免疫检查点治疗作为一种变革性的免疫治疗新策略,其在多种类型肿瘤治疗中同比表现出明显的治疗优效。然而,肿瘤免疫检查点治疗也面临很大的挑战,即免疫治疗耐药性,随着肿瘤免疫检查点治疗新机制的不断发现,新的治疗药物及其递送策略的不断研发,可望进一步大幅度提升这种策略的临床疗效。     

PD-1/PD-L1抑制剂联合含铂方案化疗治疗晚期肺癌不良反应的研究进展

长期以来,治疗无EGFR及ALK敏感基因突变的晚期非小细胞肺癌及小细胞肺癌的一线治疗方案主要为含铂的双药化疗.然而近年来,随着PD-1/PD-L1免疫抑制剂的问世,肺癌的治疗方式发生了很大的变化.PD-1/PD-L1免疫抑制剂单独用于治疗晚期非小细胞肺癌取得了较好的疗效,而一系列随机对照临床试验证实了PD-1/PD-L...     

PD-1/PD-L1抑制剂联合其他免疫检查点抑制剂治疗三阴性乳腺癌的研究进展#br#

三阴性乳腺癌（TNBC）具有全身转移率高、对常规治疗不敏感以及容易产生耐药性等特点,导致患者的预后较差。随着对机体免疫系统抗肿瘤机制及TNBC免疫特点的不断探究,以程序性细胞死亡蛋白1（PD-1）和程序性死亡蛋白配体1（PD-L1）为代表的免疫检查点抑制剂为TNBC提供了新的治疗方案,但PD-1/PD-L1抑制剂单药治疗的效果不甚理想。本文就PD-1/PD-L1抑制剂联合其他具有不同机制的免疫检查点抑制剂在TNBC患者中的应用进行综述。     

PD-1/PD-L1 pathway inhibitors in advanced prostate cancer

Introduction: Pharmacological inhibition of immune checkpoint receptors or their ligands represents a transformative breakthrough in the management of multiple cancers. However, immune checkpoint inhibitors have yet to be FDA-approved for the management of metastatic prostate cancer (PCa), the commonest non-cutaneous malignancy in men.

Areas covered: We review our current understanding of the PD-1/PD-L1 pathway in cancer, the use of anti-PD-1/PD-L1 therapeutics in PCa, and potential subgroups of PCa patients who may derive the greatest benefit from these agents (such as men with tumors that have expression of PD-L1 and/or high mutational load). We also review the prior and current clinical trials evaluating the blockade of PD-1/PD-L1 in PCa, highlighting some of the key ongoing studies of greatest relevance to the field.

Expert commentary: Clinical trials investigating PD-1/PD-L1 inhibitors should be encouraged in patients with PCa. While it is unlikely that immune checkpoint monotherapies will produce long-lasting responses in a substantial proportion of patients, there is early evidence of activity in some patient subsets. These subgroups may include those with high PD-L1 expression, those with hypermutated or microsatellite-unstable tumors, and those enriched for germline and/or somatic DNA-repair gene mutations (e.g. intraductal/ductal histology, primary Gleason pattern 5, and perhaps AR-V7-positive tumors).     

靶向垂钓技术在中药活性成分筛选中的研究进展

目的 研究近年来靶向垂钓技术（主要为配体垂钓和靶标垂钓）在中药活性成分筛选方面的进展,并做相关总结。方法 以近年来发表的相关文献为依据,对靶向垂钓-液质联用技术在中药活性成分的筛分与鉴定进行了综述。结果 目前常使用靶向垂钓技术筛分不同种类的中药活性成分,该方法具有筛分速度快、设备简单、操作简单及特异性好等优点。结论 对复杂多样的中药混合物进行分析时,利用靶向垂钓-液质联用技术可以较好地筛分目标物并鉴定其结构。     

Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy

Abstract

Cancer immunotherapy has been increasingly utilised to treat advanced malignancies. The signalling network of immune checkpoints has attracted considerable attention. Immune checkpoint inhibitors are revolutionising the treatment options and expectations for patients with cancer. The reported clinical success of targeting the T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immune modulation. Indeed, antibodies binding to PD-1 or PD-L1 have shown remarkable efficacy. However, antibody drugs have many disadvantages, such as their production cost, stability, and immunogenicity and, therefore, small-molecule inhibitors of PD-1 and its ligand PD-L1 are being introduced. Small-molecule inhibitors could offer inherent advantages in terms of pharmacokinetics and druggability, thereby providing additional methods for cancer treatment and achieving better therapeutic effects. In this review, we first discuss how PD-1/PD-L1-targeting inhibitors modulate the relationship between immune cells and tumour cells in tumour immunotherapy. Second, we discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with immunotherapy and targeted therapy. Third, this review is the first to summarise the current clinical and preclinical evidence regarding small-molecule inhibitors of the PD-1/PD-L1 immune checkpoint, considering features and responses related to the tumours and to the host immune system.

Trial registration: ClinicalTrials.gov identifier: NCT02812875.     

PD-1/PD-L1信号通路在黑色素瘤中的研究进展

细胞程序性死亡因子1(programmed death-1,PD-1)及其配体1(programmed death-ligand 1,PD-L1)是一对共刺激分子,激活细胞程序性死亡因子1及其配体1信号通路可抑制肿瘤特异性T细胞活性,有助于肿瘤细胞逃避免疫监视.而阻断该通路可以激活机体抗肿瘤免疫应答,抑制肿瘤细胞的生长...     

中药来源醛糖还原酶抑制剂的研究进展

醛糖还原酶抑制剂是治疗糖尿病并发症的重要药物之一,可通过抑制体内高血糖状态下被激活的多元醇通路中醛糖还原酶的活性而减少山梨醇的蓄积,预防和延缓糖尿病及其并发症的发生发展。中药来源的醛糖还原酶抑制剂来源更加广泛,显示了良好的应用前景。综述了2010—2020年报道的来源于中药的醛糖还原酶抑制剂及其在改善糖尿病并发症症状等方面取得的研究进展,主要包括生物碱类、黄酮类、酚酸类、皂苷类、多糖类,以及中药提取物,以期为新药研发提供依据。     

PD-1/PD-L1抑制剂在新辅助化疗中的应用进展

PD-1/PD-L1抑制剂在肿瘤的辅助治疗、晚期肿瘤治疗中都有较好的疗效,然而目前对于PD-1/PD-L1抑制剂在新辅助治疗中的作用尚不明确,本文就PD-1/PD-L1抑制剂在新辅助治疗中应用的最新进展进行综述。     

Characterization of B cell-mediated PD-1/PD-L1 interaction in pancreatic cancer patients

Pancreatic ductal adenocarcinoma (PDAC) is a common type of pancreatic cancer with one of the worst survival rate of all malignancies. Recent studies have identified that immunosuppressive B cells could employ the PD-1/PD-L1 pathway to suppress antitumour T cell responses; hence, we examined the expression and function of PD-L1 in B cells. We found that the PD-L1 expression was significantly enriched in tumour-infiltrating (TI) B cells than in peripheral blood (PB) B cells from the same patients. Additionally, the PB B cells from stage III and stage IV PDAC patients presented significantly higher PD-L1 than the PB B cells from healthy controls. High PD-L1 expression in PB B cells could be achieved by stimulation via CpG and less effectively via anti-BCR plus CD40L, but not by coculture with pancreatic cancer cell lines in vitro. Also, STAT1 and STAT3 inhibition significantly suppressed PD-L1 upregulation in stimulated B cells. CpG-stimulated PB B cells could inhibit the IFN-γ expression and proliferation of CD8 T cells in a PD-L1-dependent manner. Also, TI CD8 T cells incubated with whole TI B cells presented significantly lower IFN-γ expression and lower proliferation, than TI CD8 T cells incubated with PD-L1⁺ cell-depleted TI B cells, suggesting that PD-L1⁺ B cells could also suppress CD8 T cells in the tumour. Overall, this study identified that B cells could suppress CD8 T cells via PD-L1 expression, indicating a novel pathway of immuno-regulation in pancreatic cancer.