提高CAR-T细胞疗法抗癌活性及安全性的研究进展

经过25年的研究,以嵌合抗原受体(CAR)为基础的细胞治疗目前在治疗恶性肿瘤方面展现了巨大潜力。近几年有大量的相关试验和临床数据被报道,本综述通过对这些数据的对比和分析,讨论如何增强CAR-T细胞疗法对不可切除的恶性肿瘤的治疗效果,也对CAR-T细胞技术在恶性肿瘤临床治疗领域存在的安全问题及解决策略进行概述。     

CAR-T细胞治疗产品中复制型病毒的风险分析及控制

嵌合抗原受体T细胞（CAR-T细胞）因其在血液肿瘤中的显著疗效已成为肿瘤免疫治疗领域中的国际研究新热点,成为肿瘤治愈新的希望。目前,在CAR-T细胞产品的生产中,通常是利用逆转录病毒载体或慢病毒载体将CAR基因高效地导入T细胞中,但在使用这些病毒载体的同时也带来了CAR-T产品污染复制型逆转录病毒（RCR）或复制型慢病毒（RCL）的潜在风险。虽然随着病毒载体设计及生产体系的不断改进,这种风险已大大降低,但仍不能完全排除。因此,监管机构要求对于临床使用的慢病毒或逆转录病毒载体、转导的CAR-T细胞产品以及患者均要进行复制型病毒的检测。本文主要通过分析复制型病毒污染检测的必要性、降低复制型病毒污染风险的措施、复制型病毒检测的阶段以及检测方法等方面,提出在CAR-T细胞生产过程中控制RCR/RCL的策略,以供CAR-T细胞产品研发者参考。     

T细胞恶性肿瘤的嵌合抗原受体T细胞治疗研究进展

T细胞恶性肿瘤具有高度恶性、预后差等特点,对于复发 / 难治性患者当前最有效的治疗手段是造血干细胞移植,但往往伴随着诸多移植相关风险,故探索更多安全、有效的疗法迫在眉睫。嵌合抗原受体T细胞治疗(chimeric antigen receptor T cell therapy,CAR-T cell therapy)作为一种近年来较新颖的免疫疗法,在复发/难治性B细胞恶性肿瘤及多发性骨髓瘤中已展现出了巨大临床受益。然而对于T细胞恶性肿瘤,CAR-T 细胞治疗仍处于临床前和早期临床阶段,并面临着重重困难。现阐述目前T细胞恶性肿瘤的CAR-T细胞治疗的研究进展,旨在为临床治疗相关疾病提供一定参考。     

嵌合抗原受体T细胞功能设计与运用的研究进展

嵌合抗原受体T细胞(chimeric antigen receptor engineered T cell,CAR-T)治疗在B细胞恶性肿瘤治疗的临床试验中取得了巨大成功,引起了业界极大的关注.文章就CAR功能区域,CAR功能设计和CAR-T运用等方面研究进展进行综述.     

基于CAR的细胞治疗在自身免疫性疾病中应用的研究进展北大核心CSCD

随着2017年首款嵌合抗原受体T细胞(CAR-T)产品上市,免疫细胞治疗跨入新时代,给全球数以万计的肿瘤患者带来了治疗新希望。目前,CAR-T细胞产品已在急性B淋巴细胞白血病、B细胞非霍奇金淋巴瘤、多发性骨髓瘤等血液系统恶性肿瘤治疗中取得了显著效果,在治疗实体瘤和感染性疾病(如HIV感染)中也取得了一定进展。尽管病因不同,部分自身免疫性疾病(AIDs)与血液学肿瘤都可因B淋巴细胞/浆细胞功能异常而发病,CAR-T细胞产品在治疗血液学肿瘤中取得的成功向科学家们提示了其治疗AIDs的潜力。近期CAR-T细胞在系统性红斑狼疮等AIDs的治疗中取得了突破性进展,本文将对基于CAR的细胞疗法在自身免疫性疾病中的应用研究进展进行介绍并对未来的发展方向进行展望。     

基因修饰体细胞国内外临床研究和相关产业现状及未来发展趋势

基因编辑技术可针对性增强体细胞的靶向性,一定程度上解决了传统过继性免疫疗法在肿瘤等多种疾病治疗中显露出的靶向性差等问题.最具代表性的是嵌合抗原受体T细胞(CAR-T)免疫疗法,其在血液系统肿瘤治疗中已取得良好疗效,此外,T细胞受体基因工程化的T细胞(TCR-T)、基因修饰的树突状细胞以及基因修饰的干细胞在多种疾病治疗的...     

降低亲和力提高HER2-CAR-T细胞治疗的安全性

目的 探讨降低CAR-T细胞亲和力是否能有效提高其杀伤特异性,减少"脱靶效应"。方法 构建靶向HER2的中等亲和力和高亲和力的La-G3HER2-CAR和Ha-G3HER2-CAR并电穿孔转染T细胞,采用Western Blot、FCM技术和xCELLigence RTCA DP进行CAR载体表达和杀伤功能检测。结果 La-G3HER2-CAR-T细胞和Ha-G3HER2-CAR-T细胞分别表达43000和58000的外源CAR载体片段,转染效率分别为58.1%和69.0%。高亲和力的Ha-G3HER2-CAR-T细胞对高、中、低水平表达HER2的6种靶细胞均有效杀伤,而低亲和力的La-G3HER2-CAR-T细胞高效杀伤HER2高表达的SK-OV-3和BT474细胞,对HER2中表达的MDA-MB-231和HCC-202的杀伤作用较弱,而对低水平表达HER2的MCF-7和293细胞不杀伤。进一步的机制研究发现,HER2中水平表达的MDA-MB-231细胞共培养对La-G3HER2-CAR-T细胞和Ha-G3HER2-CAR-T细胞激活和细胞因子分泌诱导水平不同(CD107a:8.2% vs 71.6%; IFN-γ:66.3% vs 83.4%; TNF-α:73.4% vs 94.1%)。结论 中等亲和力La-G3HER2-CAR-T细胞比高亲和力的Ha-G3HER2-CAR-T细胞的杀伤作用特异性更强,降低CAR-T细胞的亲和力可以提高治疗的安全性。     

嵌合抗原受体T细胞疗法治疗多发性骨髓瘤的研究进展

多发性骨髓瘤(multiple myeloma, MM)是由浆细胞恶性增殖引起的恶性肿瘤, 可在骨髓中积累导致骨髓衰竭。MM的治疗通常包括免疫调节剂和造血干细胞移植等方式, 但是疗效并不理想。嵌合抗原受体T细胞疗法是近年来出现的一种新型免疫疗法, 通过体外基因编辑技术改造患者的T细胞, 使其能够特异性识别肿瘤细胞的表面抗原, 从而达到靶向杀伤肿瘤细胞的目的。此文主要就嵌合抗原受体T细胞在MM治疗中的应用及靶点作一介绍。     

Anti-tumour effect of the fourth-generation chimeric antigen receptor T cells targeting CD133 against cholangiocarcinoma cells

Current treatment of cholangiocarcinoma (CCA) – a lethal bile duct cancer – is ineffective because the disease is usually diagnosed at late and advanced stage. Thus, a novel therapeutic modality is urgently required. Fourth-generation chimeric antigen receptor (CAR4) T cells was created to target CD133, a well-known cancer stem cell marker, that is highly expressed and associates with cancer progression. The anti-CD133-CAR4 T cells showed high efficacy against CD133-expressing CCA cells. Tumour cell lysis occurred in a dose- and CD133 antigen-dependent manner, and significantly higher, up to 57.59% ± 9.62 at effector to target ratio of 5:1 in a CCA cell line – KKU-213A cells, compared to mock control (p = 0.008). Similarly, significant IFN-γ (p = 0.011) and TNF-α (p = 0.002) upregulation was observed upon tumour treatment. The effectiveness of our anti-CD133-CAR4 T cells will be beneficial not only for CD133-expressing CCA, but also for other CD133-expressing tumours. This study may guide future in vivo study and clinical trials.     

核素药物在肿瘤细胞治疗中的应用研究进展

目前,用于医学诊疗的核素种类繁多,在肿瘤细胞的诊断和治疗等方面都发挥着显著且有效的作用。由于肿瘤细胞的异质性和肿瘤微环境的高度可变性,使得提供精确诊断和靶向杀伤等功能的放射性核素偶联药物成为肿瘤精准医疗中不可或缺的手段和工具。结合近年来核素药物的临床前研究和临床试验,详细介绍诊断类核素在肿瘤细胞治疗中的应用,以及治疗类核素与其他肿瘤细胞疗法的协同治疗的应用,为核素药物的配对诊疗研究及临床转化提供发展方向。     

免疫检查点B7-H3在癌症中作用研究进展

免疫检查点是指在免疫细胞上表达,能调节免疫激活程度的一系列分子,其对调节免疫作用至关重要。越来越多的免疫检查点被发现在癌细胞上有异常表达,并与癌症进展密切相关。基于这些免疫检查点,许多靶向药物被开发,如抗体药物、嵌合抗原受体T细胞（CAR-T）、抗体偶联药物（ADC）等。B7-H3是近年来发现的新免疫检查点,在多种肿瘤组织上均发现有异常表达,其不仅具有免疫调节功能,也能通过一些非免疫机制促使肿瘤细胞增生、逃逸免疫反应、产生耐药性和转移。综述B7-H3在癌症进展中发挥的作用及其机制研究进展,以期为靶向B7-H3新药的开发提供参考。     

The Impact of Product and Process Related Critical Quality Attributes on Immunogenicity and Adverse Immunological Effects of Biotherapeutics

The pharmaceutical industry has experienced great successes with protein therapeutics in the last two decades and with novel modalities, including cell therapies and gene therapies, more recently. Biotherapeutics are complex in structure and present challenges for discovery, development, regulatory, and life cycle management. Biotherapeutics can interact with the immune system that may lead to undesired immunological responses, including immunogenicity, hypersensitivity reactions (HSR), injection site reactions (ISR), and others. Many product and process related critical quality attributes (CQAs) have the potential to trigger or augment such immunological responses to the product. Tremendous efforts, both clinically and preclinically, have been invested to understand the impact of product and process related CQAs on adverse immunological effects. The information and knowledge are critical for the implementation of Quality by Design (QbD), which requires risk assessment and establishment of specifications and control strategies for CQAs. A quality target product profile (QTPP) that identifies the key CQAs through process development can help assign severity scores based on safety, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of the molecule. Gaps and future directions related to biotherapeutics and emerging novel modalities are presented.     

Emerging role of natural products in cancer immunotherapy

Cancer immunotherapy has become a new generation of anti-tumor treatment, but its indications still focus on several types of tumors that are sensitive to the immune system. Therefore, effective strategies that can expand its indications and enhance its efficiency become the key element for the further development of cancer immunotherapy. Natural products are reported to have this effect on cancer immunotherapy, including cancer vaccines, immune-check points inhibitors, and adoptive immune-cells therapy. And the mechanism of that is mainly attributed to the remodeling of the tumor-immunosuppressive microenvironment, which is the key factor that assists tumor to avoid the recognition and attack from immune system and cancer immunotherapy. Therefore, this review summarizes and concludes the natural products that reportedly improve cancer immunotherapy and investigates the mechanism. And we found that saponins, polysaccharides, and flavonoids are mainly three categories of natural products, which reflected significant effects combined with cancer immunotherapy through reversing the tumor-immunosuppressive microenvironment. Besides, this review also collected the studies about nano-technology used to improve the disadvantages of natural products. All of these studies showed the great potential of natural products in cancer immunotherapy.     

Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.