肿瘤免疫疗法中免疫检查点的研究进展

免疫检查点(immune chenkpoint)是存在于免疫系统中的抑制性信号通路,对外周组织中免疫反应强度、持续性予以调节,防止组织损伤,并在维持自身抗原耐受性的过程中发挥作用。T细胞识别、清除肿瘤的过程受到诸多信号通路、配体/受体的严密调控。免疫检查点疗法就是一类通过调节T细胞活性来提高抗肿瘤免疫反应的治疗方法。目前,通过抑制免疫检查点阻断信号以调节T细胞活性增强其抗肿瘤效应是肿瘤治疗热点,例如利用CTLA-4(cytotoxic T lymphocyte antigen4)、PD-1(programmed cell death1)、PD-L1(programmed cell death 1 ligand)的拮抗剂以及其它药物干扰免疫检查点,可直接刺激细胞毒性T细胞的活化进而启动抗肿瘤免疫,介导持续的肿瘤抑制过程。而联合使用免疫检查点阻断剂加强肿瘤抑制效果也在进行深入研究。免疫检查点信号通路的生物学机制目前获得诸多进展,本文就一些已应用于临床的免疫检查点及其它新型免疫检查点的研究进展加以综述。     

癌症免疫疗法最新进展

免疫疗法在癌症治疗中具有独特优势,故越来越受到制药企业和研究机构的青睐,研发的癌症免疫治疗药物新品种也在不断扩增。介绍癌症免疫治疗产品研发的最新动态。     

基于核酸适配体的肿瘤免疫治疗进展

肿瘤免疫治疗是通过调节机体的免疫功能来控制和杀伤肿瘤的一种治疗手段。针对免疫检查点的治疗等一系列临床突破使得肿瘤的免疫治疗受到了广泛重视。目前,抗体治疗和过继性细胞治疗是肿瘤免疫治疗的主要方式,但是这些方法仍具有副作用较强,实体瘤治疗难以实现,治疗费用高昂等缺点。因此改进和发展更加高效、安全、低成本的新技术仍十分必要。适配体是利用指数富集的配体系统进化技术筛选得到的单链寡核苷酸,有核酸"抗体"之称。适配体具有低免疫原性、组织穿透力强、易于化学合成与修饰等优势,且与其靶标的结合具有较好亲和力和特异性,可像抗体一样实现肿瘤的免疫治疗。对适配体在肿瘤免疫治疗相关技术中的新应用作一综述,主要包括基于免疫检查点的抗肿瘤作用、双特异性适配体的肿瘤免疫治疗、适配体靶向递送siRNA的肿瘤免疫治疗和适配体联合抗体的肿瘤免疫治疗等方面。     

以Ⅳ型胶原酶为靶点的小型化单抗免疫偶联物的抗肿瘤作用

Ⅳ型胶原酶与肿瘤的侵袭、转移以及新血管生成等过程密切相关. 以Ⅳ型胶原酶为分子靶点, 利用小鼠抗Ⅳ型胶原酶单抗构建了小型化的Fab'片段与高效抗肿瘤抗生素力达霉素(LDM)的免疫偶联物 (Fab'-LDM). 偶联物的分子量约为65 kD, 偶联分子比为1︰1. 以ELISA方法检测, Fab'-LDM偶联物保留了单抗Fab′片段对肝癌22(H22)细胞的免疫结合活性; 以MTT法测定, Fab'-LDM偶联物对肝癌22细胞显示出更强的细胞毒性. 动物体内试验观察对小鼠移植性肝癌22的疗效, 小鼠皮下接种肿瘤, 24 h后开始给药(静脉注射2次, 分别在接种后1和8天), Fab'-LDM偶联物0.025, 0.05和0.10 mg/kg剂量组的抑瘤率分别为76.7%, 93.3%和94.8%, 而游离LDM 0.05 mg/kg的抑瘤率为76.1%; 另一批实验于接种肿瘤96 h后开始给药(静脉注射2次, 分别在接种后4和11天), Fab'-LDM偶联物0.025和0.05 mg/kg组的抑瘤率分别为74.2%和80.9%, 而LDM 0.05 mg/kg组的抑瘤率为60.5%. Fab'-LDM偶联物0.05 mg/kg可显著延长荷瘤小鼠的生存时间, 与同等剂量的游离LDM相比, 延长生存时间的效果更强(P < 0.05). 以上结果表明, 以Ⅳ型胶原酶为靶点的小型化单抗免疫偶联物在肿瘤的实验治疗中有显著的疗效.     

单克隆抗体的诊断与治疗应用的近况

70年代建立淋巴细胞杂交瘤技术以来,已制备了大量的单克隆抗体(以下简称单抗)。这些单抗已通过放射免疫测定法,酶联免疫吸附试验、免疫细胞病理学和流式细胞计数,进行基础医学研究和体外诊断疾病;还通过偶联物或直接使用单抗进行了体内诊断与治疗疾病的研究。     

核酸适配体介导的肿瘤免疫治疗研究进展

肿瘤免疫治疗是一种新的肿瘤治疗方式,在临床治疗中具有重要意义和应用前景,主要包括过继性细胞免疫治疗、肿瘤疫苗和抗体肿瘤免疫治疗。抗体在肿瘤免疫治疗中应用广泛,但其价格昂贵,质量易受不同批次的影响且存在免疫原性。核酸适配体(aptamer)是一类能与靶标高特异性高亲和力结合的短的单链寡核苷酸,素有“化学抗体”之称。核酸适配体易合成且成本低,质量稳定且免疫原性低,基于这些优势近年来也被开发用于肿瘤免疫治疗。本文综述了核酸适配体在肿瘤免疫治疗中的进展,主要包括核酸适配体通过靶向免疫检查点、共刺激受体、细胞因子、递送小干扰RNA (small interfering RNA,siRNA),间接调控肿瘤免疫进程,以及将核酸适配体修饰于细胞膜上直接介导免疫细胞靶向杀伤等。核酸适配体以多种方式在肿瘤免疫治疗中发挥作用,有潜力被开发用于临床治疗。     

双特异性抗体在肿瘤治疗中的研究

双特异性抗体(bispecific antibody,BsAb)有两个抗原结合位点,其中一个位点可与靶细胞表面抗原结合,另一个位点则可与载荷物(如效应细胞,分子等)结合。将BsAb应用于肿瘤治疗,发挥抗肿瘤效应的思想已有二十多年历史,随着对效应细胞生物学了解的加深和抗体工程的飞速发展,各种形式的BsAb相继出现,多种BsAb药物已进入临床初期试验或治疗使用阶段。本文就BsAb的各种新形式及其在肿瘤治疗中的应用新进展作简要概述。     

靶向攻击肿瘤的免疫疗法

用单克隆抗体治疗癌症一直是肿瘤免疫学研究的热点之一。以往的抗体治疗均以癌细胞表面蛋白为靶标,因为全抗体分子太大而不能穿过细胞膜。最近新加坡科技研究局下属的分子与细胞生物学研究所(IMCB)曾琦博士及其团队的研究发现,抗体治疗不仅能以胞外癌蛋白为靶标,也能以胞内癌蛋白为靶标,进入胞内杀死癌细胞,从而抑制癌细胞的生长;这些发现对癌症的免疫治疗具有突破性的意义。现将其主要内容摘录如下,供我国学者参考。读者有意阅读原文请看:[Ferrone S.Hidden immunotherapy targets challenge dogma,Sci Transl Med,2011,3(99):99ps38]     

单克隆抗体的研究进展

单克隆抗体是一种由骨髓瘤细胞和带有抗体的B淋巴细胞结合形成的杂交瘤细胞,简称单抗。首先,本文对单克隆抗体的研究发展历程进行了分析和探讨,指出单克隆抗体的发展历程包括鼠源性单抗、嵌合抗体、人源化抗体以及人源性抗体这四大阶段,分别对其优缺点进行了说明;接下来,又对单克隆抗体在临床上的应用进行了说明,从疾病诊断方面及疾病的治疗两方面进行探讨。     

肿瘤抗体研究进展

近几十年以来,随着生命科学的发展,已被生理学家们对肿瘤及治疗肿瘤的认识不断加深,从化学药物到天然植物药(如紫杉醇),再到当前的免疫靶向治疗药物(如以肿瘤细胞膜为靶点和以肿瘤血管生成为靶点的抗体药物)。科学家们通过对抗体分子的人源化改造,新型抗体分子的研究,药物可分解性无毒性等多方面的研究,使得抗肿瘤药物进入了一个全新的新时期,寄望研究出对癌症患者更友好更有效的药物。     

肝癌免疫治疗的研究进展

肝细胞肝癌是全球发病率和死亡率最高的恶性肿瘤之一,发病率和死亡率呈逐年上升趋势。我国是肝癌大国,每年肝癌的死亡病例数位居全球第一。免疫治疗是继手术、化疗和放疗之后新兴的癌症治疗手段,其通过解除肿瘤微环境对免疫细胞的抑制作用并激活机体免疫功能,实现控制和杀伤肿瘤细胞。常用的免疫治疗的方法有免疫检查点治疗、过继免疫治疗和肿瘤疫苗治疗等。与传统治疗手段相比,免疫治疗因具有增强机体免疫功能、延缓肿瘤进展、延长患者生存时间等优点,逐渐成为基础和临床研究的热点。文中就免疫治疗在肝癌领域的研究进展作一综述。     

IgE immunotherapy: A novel concept with promise for the treatment of cancer

The importance of antibodies in activating immune responses against tumors is now better appreciated with the emergence of checkpoint blockade antibodies and with engineered antibody Fc domains featuring enhanced capacity to focus potent effector cells against cancer cells. Antibodies designed with Fc regions of the IgE class can confer natural, potent, long-lived immune surveillance in tissues through tenacious engagement of high-affinity cognate Fc receptors on distinct, often tumor-resident immune effector cells, and through ability to activate these cells under tumor-induced Th2-biased conditions. Here, we review the properties that make IgE a contributor to the allergic response and a critical player in the protection against parasites, which also support IgE as a novel anti-cancer modality. We discuss IgE-based active and passive immunotherapeutic approaches in disparate in vitro and in vivo model systems, collectively suggesting the potential of IgE immunotherapies in oncology. Translation toward clinical application is now in progress.     

Antibody-drug therapeutic conjugates: Potential of antibody-siRNAs in cancer therapy

Codelivery is a promising strategy of targeted delivery of cytotoxic drugs for eradicating tumor cells. This rapidly growing method of drug delivery uses a conjugate containing drug linked to a smart carrier. Both two parts usually have therapeutic properties on the tumor cells. Monoclonal antibodies and their derivatives, such as Fab, scFv, and bsAb due to targeting high potent have now been attractive candidates as drug targeting carrier systems. The success of some therapeutic agents like small interfering RNA (siRNA), a small noncoding RNAs, with having problems such as enzymatic degradation and rapid renal filtration need to an appropriate carrier. Therefore, the aim of this study is to review the recent enhancements in development of antibody drug conjugates (ADCs), especially antibody–siRNA conjugates (SRCs), its characterizations and mechanisms in innovative cancer therapy approaches.     

PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy

Over the course of past few years, cancer immunotherapy has been accompanied with promising results. However, preliminary investigations with respect to immunotherapy concentrated mostly on targeting the immune checkpoints, nowadays, emerge as the most efficient strategy to raise beneficial antitumor immune responses. Programmed cell death protein 1 (PD-1) plays an important role in subsiding immune responses and promoting self-tolerance through suppressing the activity of T cells and promoting differentiation of regulatory T cells. PD-1 is considered as an immune checkpoint and protects against autoimmune responses through both induction of apoptosis in antigen-specific T cells and inhibiting apoptosis in regulatory T cells. Several clinical trials exerting PD-1 monoclonal antibodies as well as other immune-checkpoint blockades have had prosperous outcomes and opened new horizons in tumor immunotherapy. Nonetheless, a bulk of patients have failed to respond to these newly emerging immune-based approach and the survival rate was not satisfying. Additional strategies, especially combination therapies, has been initiated and been further promising. Attempts to identify novel and well-suited predictive biomarkers are also sensed. In this review, the promotion of cancer immunotherapy targeting PD-1 immunoinhibitory pathway is discussed.     

Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes

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Addressing cancer immunotherapy research in Iran: adoptive cell therapy on the horizon

Recent advances in immunotherapeutic modalities have profoundly changed the prospect of cancer treatment. These modalities mainly focus on modulating the immune response toward tumor cells by using monoclonal antibodies, cancer vaccines, adoptive cell transfer or combination of these methods. In the last few years, Iranian scientists have conducted several projects in these arenas. Here, we provide an overview of these studies and analyze the quality and trend of publications in each sub-specialty of the field. In addition, the contribution of different universities and scientific institutes is assessed. This study may benefit scientific community and policymakers to plan future cancer immunotherapies in Iran and other countries.     

Cancer immunotherapy takes a multi-faceted approach to kick the immune system into gear

Cancer accounts for about every fourth death in the United States, with approximately 1,500 people dying each day as a result of this disease. Despite some progress in the last decades, these numbers alone undoubtedly demonstrate the urgent need for new and more efficient treatments. Immunotherapy aims to activate an efficient immune response against tumors or even prevent cancers from occurring in the first place. It is a growing field currently flourishing with several successful trials, some of which have led to the recent approval of new anti-cancer drugs by the Food and Drug Administration (FDA). This review addresses the manifold strategies that immunotherapy has taken in the past and discusses the most recent achievements in the field.     

Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy

Ganglioside GD2 is highly expressed on neuroectoderm-derived tumors and sarcomas, including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing’s sarcoma in children and adolescents, as well as liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas in adults. Since GD2 expression in normal tissues is restricted to the brain, which is inaccessible to circulating antibodies, and in selected peripheral nerves and melanocytes, it was deemed a suitable target for systemic tumor immunotherapy. Anti-GD2 antibodies have been actively tested in clinical trials for neuroblastoma for over the past two decades, with proven safety and efficacy. The main limitations have been acute pain toxicity associated with GD2 expression on peripheral nerve fibers and the inability of antibodies to treat bulky tumor. Several strategies have been developed to reduce pain toxicity, including bypassing complement activation, using blocking antibodies, or targeting of O-acetyl-GD2 derivative that is not expressed on peripheral nerves. To enhance anti-tumor efficacy, anti-GD2 monoclonal antibodies and fragments have been engineered into immunocytokines, immunotoxins, antibody drug conjugates, radiolabeled antibodies, targeted nanoparticles, T-cell engaging bispecific antibodies, and chimeric antigen receptors. The challenges of these approaches will be reviewed to build a perspective for next generation anti-GD2 therapeutics in cancer therapy.     

IFNγ-induced stem-like state of cancer cells as a driver of metastatic progression following immunotherapy

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