免疫检查点抑制剂在恶性淋巴瘤中的应用研究进展*

免疫检查点是一类免疫抑制性分子,通过调节免疫反应的强度和广度,从而避免正常组织的损伤和破坏。近年来研究发现肿瘤细胞可通过激活免疫检查点活性,从而逃避免疫系统的监视。免疫检查点抑制剂则通过拮抗免疫检查点蛋白,促进T 细胞活化,进而产生抗肿瘤免疫效应。免疫检查点抑制剂在多种实体瘤的治疗方面已显示出良好的疗效。在淋巴瘤的治疗领域,虽然尚处于起步阶段,检查点抑制剂亦显示出良好的疗效及安全性。本文主要总结免疫检查点蛋白细胞毒性T 淋巴细胞相关抗原- 4（cytotoxic T lymphocyte associated antigen-4,CTLA- 4）、程序性死亡受体- 1（programmed death- 1,PD- 1）及其程序性死亡受体配体- 1（programmed death ligand 1,PD-L1）的生物学活性,并介绍相应抗体药物在淋巴瘤研究中的进展。      

PD-1/PD-L1抑制剂在前列腺癌免疫治疗中的研究进展

前列腺癌（prostate cancer,PCa）发病率呈逐年上升趋势,前列腺癌免疫治疗已成为继外科、放疗、化疗之后的第四种治疗方法。作为当今肿瘤免疫治疗领域最具有研究前景的免疫检查点抑制剂中的程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡配体-1（programmed cell death-ligand1,PD-L1）抑制剂,通过阻断PD-1与其配体PD-L1结合,从而终止T细胞的负性调控信号,使T细胞的活性恢复,进而逆转肿瘤免疫逃逸机制,恢复自身免疫应答,最后起到抑制和杀伤肿瘤的作用。本文就目前应用于前列腺癌临床试验的PD-1/PD-L1抑制剂的现况和临床疗效研究进展进行综述。      

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可能机制的探索、心脏毒性的检测方法和PD-1/PD-L1所致心脏毒性的治疗等方面进行综述。     

免疫检查点抑制剂在前列腺癌治疗中的研究进展北大核心

肿瘤诱导的免疫抑制状态在包括前列腺癌(PC)在内的癌症的发病机制中起着至关重要的作用。细胞毒T淋巴细胞相关抗原4(CTLA-4)和程序性死亡受体-1(PD-1)及其配体PD-L1是近年来研究比较透彻的免疫检查点分子。通过阻断免疫检查点(主要针对CTLA-4和PD-1/PD-L1通路)来增强细胞介导的抗肿瘤免疫成为研究热点。本文主要综述了免疫检查点抑制剂及其用于晚期前列腺癌的理论基础和前列腺癌治疗中的进展。     

阻断T细胞活化抑制通路治疗恶性肿瘤新进展

肿瘤免疫治疗近年来取得了较大进展,阻断T细胞活化抑制通路的抗程序性死亡受体-1（programmed death-1,PD-1）/程序性死亡配体-1（programmed death-ligand1,PD-L1）及细胞毒性T淋巴细胞抗原-4（cytotoxic T lymphocyte antigen-4,CTLA-4）等单克隆抗体（也被称为免疫检查点抑制剂）应用于临床,有些抗体已纳入特定肿瘤的一线治疗。本文就免疫检查点抑制剂（immune checkpoint inhibitors,ICPIs）的作用机制、临床研究结果、免疫相关不良事件等方面的最新进展进行综述,从而分析该领域所面临的问题及未来发展前景。      

PD-1/PD-L1抑制剂联合治疗在癌症免疫治疗中的研究进展

程序性死亡蛋白-1(programmed cell death-1,PD-1)是一种免疫检查点的负性调控因子,通过与其配体PD-L1/PD-L2结合,抑制T细胞的免疫功能,而PD-1抑制剂则可恢复免疫系统的抗肿瘤作用。较其他治疗手段而言,PD-1抑制剂有显著的临床疗效,然而其仍然存在不足,即目前仍有很大一部分癌症患者对PD-1抑制剂治疗是无效的。研究表明联合治疗可改善PD-1抑制剂单药治疗的有效率。联合治疗包括联合免疫检查点抑制剂、放疗、化疗、癌症疫苗和其他癌症治疗方法。FDA已批准了PD-1抑制剂联合CTLA-4阻断剂治疗,其抗肿瘤效率与肿瘤微环境以及免疫相关因子有关,但关于免疫系统,特别是T细胞对肿瘤阳性响应率的潜在作用机制研究甚少。本文将综述免疫检查点PD-1抑制剂的临床疗效以及其影响因素、作用机制以及PD-1抑制剂联合其他治疗的研究现状。     

免疫检查点抑制剂在复发或转移性头颈部鳞状细胞癌治疗中的进展

随着对肿瘤微环境与免疫治疗间复杂相互作用的认识，免疫检查点在头颈部鳞状细胞癌（HNSCC）治疗中的作用越来越受到关注。以程序性死亡蛋白-1（PD-1）/程序性死亡蛋白配体-1（PD-L1）、细胞毒性T淋巴细胞相关蛋白-4（CTLA-4）、T细胞免疫球蛋白黏蛋白分子-3（TIM-3）为靶点的免疫检查点抑制剂，如帕博利珠单抗、度伐利尤单抗、特瑞普利单抗、伊匹木单抗、LY3321367等，可作为单一疗法和联合疗法应用于复发或转移性HNSCC的治疗。进一步研究免疫检查点抑制剂在临床治疗中的疗效与安全性，有望为复发或转移性HNSCC患者的治疗提供更有效的策略。     

非小细胞肺癌免疫检查点抑制剂相关性肺炎研究进展

摘 要：免疫检查点抑制剂主要包括细胞毒性T淋巴细胞抗原4（CTLA-4）抗体和程序性细胞死亡蛋白-1（PD-1）及配体（PD-L1）单克隆抗体,在非小细胞肺癌治疗中表现出良好疗效。免疫检查点抑制剂相关性肺炎（checkpoint inhibitor-related pneumonitis,CIP）临床发生率低,但易造成免疫治疗延迟或终止,严重可导致死亡。接受免疫检查点抑制剂治疗后出现新发呼吸道症状的患者必须高度怀疑肺炎。该综述简要介绍了CIP的流行病学、机制和临床特点等,并讨论CIP的治疗策略。     

免疫检查点抑制剂抗肿瘤治疗中相关性心脏毒性的研究进展

程序性死亡因子-1(PD-1)及程序性死亡受体配体1(PD-L1)抑制剂通过阻断PD-1与PD-L1的相互作用,使负向调控信号受阻,刺激免疫系统,使T淋巴细胞继续杀死肿瘤细胞,从而增强机体的免疫反应,但这也破坏了正常免疫系统的平衡,造成免疫耐受紊乱,发生免疫相关不良反应.本文结合目前最新的研究进展,主要介绍免疫抑制剂——PD-1在抗肿瘤治疗中所介导的心脏毒性,从机制、临床表现、监测与治疗、尚待解决的问题等方面进行综述.     

基于PD-1/PD-L1 抑制剂的肺癌免疫治疗预测标志物的研究进展

[摘要] 近年来,免疫检查点抑制剂在肺癌治疗中取得突破性进展,正迅速改变着肺癌的治疗模式,也标志着免疫治疗2.0 时代的到来。新的肿瘤治疗模式对精准医学提出更高要求,对程序性死亡受体1（programmed death 1, PD-1）/程序性死亡配体1（programmed death ligand 1, PD-L1）抑制剂预后生物标志物也在不断地探索之中,主要包括以下几个方面：PD-L1 表达水平、肿瘤基因组异质性与肿瘤新抗原、T细胞特点、肿瘤微环境以及机体整体状态等。本文将针对目前PD-1/PD-L1 抑制剂在肺癌免疫治疗中的潜在生物标志物最新临床研究进展及其研究前景进行综述。     

免疫检查点抑制剂在淋巴瘤中的研究进展

肿瘤细胞利用免疫检查点通路来逃避宿主免疫系统并抑制免疫细胞功能.癌细胞表达程序性细胞死亡蛋白配体1/2(programmed death-ligand 1/2,PD-L1/PD-L2)与细胞毒性 T 细胞上存在的程序性细胞死亡蛋白 1(programmed cell death protein-1,PD-1)结合,触发...     

Current situation of programmed cell death protein 1/programmed cell death ligand 1 inhibitors in advanced triple-negative breast cancer

Triple-negative breast cancer(TNBC) has the worst prognosis among all molecular types of breast cancer. Because of the strong immunogenicity of TNBC cells, programmed death 1/programmed death ligand 1(PD-1/PD-L1)inhibitors, two kinds of immune checkpoint blockade agents, might help improve the prognosis of TNBC.However, how to better use PD-1/PD-L1 inhibitors and select patients who may benefit from treatment options remains controversial. This article summarizes published clinical studies in wh...     

The evolving role of PD-L1 testing in patients with metastatic urothelial carcinoma

Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway improve clinical outcomes in patients with locally advanced/metastatic urothelial carcinoma (UC). PD-L1 complementary or companion diagnostic assays are now available for anti–PD-1 and anti–PD-L1 antibodies and these assays enable testing at diagnosis. The role of PD-L1 testing in UC is, however, the subject of much discussion within the medical community, particularly in light of recent restrictions on recruitment of PD-L1–low patients in clinical trials of atezolizumab and pembrolizumab as first-line therapy, and the European Medicines Agency and US Food and Drug Administration limiting use of these agents as first-line therapy in cisplatin-ineligible patients to those with high PD-L1 expression. We explore the evolving evidence for PD-L1 expression testing in UC and the role of PD-L1 expression in both tumor cells and tumor-infiltrating immune cells. We review clinical data on the prognostic and predictive value of PD-L1 expression in response to anti–PD-1/PD-L1 agents as first- and second-line therapy, considering issues such as the differences among complementary diagnostic assays in terms of the type of cells scored, antibodies used, and cutoff values. We consider how PD-L1 testing fits into decision-making and the potential of emerging biomarkers in UC. We conclude that, based on the scientific rationale for its use and evidence from clinical trials, PD-L1 testing provides enriched information on the patients most likely to benefit from immune checkpoint blockade and should be routinely offered to patients with metastatic UC.     

The promising role of nivolumab in renal cell cancers

The therapeutic efficacy of checkpoint inhibitors across numerous tumor types has resulted in approval for neoplasms such as melanoma and lung cancer. Nivolumab is a fully humanized IgG4 antibody that inhibits immune checkpoint between programmed death 1 (PD-1) on T cells and PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2) on immune and cancer cells. Motzer and Colleagues published the findings of Nivolumab versus everolimus in advanced kidney cancer in the November issue of the New England Journal of Medicine. This trial showed that nivolumab resulted in better median overall survival of 25 months compared to everolimus at 19.6 months, with a hazard ratio for death at 0.73, meeting pre-specified criterion for superiority in favor of nivolumab. These findings mark the defining beneficial role of immune checkpoint inhibitor therapy in metastatic kidney cancer.     

PD-1/PD-L1抑制剂治疗淋巴瘤的研究进展

免疫检查点抑制剂已被批准用于多种难治性实体肿瘤的治疗,如恶性黑色素瘤、肺癌、胰腺癌、肾癌等。其在复发/难治性淋巴瘤的治疗方面也展现出广阔的应用前景。程序性死亡受体-1及其配体(PD-1/PD-L1)通路是免疫检查点抑制治疗(checkpoint blockade therapy,CBT)的关键性通路之一。肿瘤细胞可通过PD-1/PD-L1通路抑制T细胞活性,阻断免疫应答,从而实现免疫逃逸,最终促进肿瘤的发生、发展。新近研究发现PD-1/PD-L1通路在复发/难治性霍奇金淋巴瘤（Hodgkin lymphoma,HL）和部分非霍奇金淋巴瘤（non-Hodgkin lymphoma,NHL）中也发挥着重要作用。本文将简单介绍PD-1/PD-L1通路的生物学活性,总结针对该通路的免疫疗法在恶性淋巴瘤治疗中的研究进展。     

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。     

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...     

Rationale for anti-OX40 cancer immunotherapy

Immune checkpoint blockade with antagonistic monoclonal antibodies (mAbs) targeting B7 immunoglobulin superfamily molecules (CTLA-4, PD-1, and PD-L1) generate long lasting anti-tumour immune responses translating into clinical benefit across many cancer types. However, many patients are primarily resistant to immune checkpoint blockade –based monotherapy and many others will eventually relapse. Therefore, new immunostimulatory targets are needed to overcome primary and secondary resistance to immunotherapy. Besides the B7 co-inhibitory receptors, the tumour necrosis factor receptor superfamily contains many other immune checkpoints, which could become the next generation immunomodulators. Among them stands OX40 (CD134), a co-stimulatory molecule that can be expressed by activated immune cells. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials. Accumulating preclinical evidence supports their clinical development. However, conflicting results and controversies between in vitro and in vivo data point to the need for comprehensive ancillary studies to be performed in upcoming clinical trials to better understand the mechanism of action of anti-OX40 mAbs-based therapy.