新型溶瘤病毒HSV-1-ab-VISTA的构建及其抗肿瘤作用

目的 探讨携带免疫检查点VISTA抗体的溶瘤病毒HSV-1-ab-VISTA在小鼠(C57BL/6J)移植瘤模型中的抗肿瘤效果。方法 利用CRIPSR-Cas9基因编辑技术制备携带VISTA分子抗体的HSV-1-ab-VISTA溶瘤病毒；琼脂糖凝胶电泳检测VISTA抗体的基因组片段大小；蛋白免疫印迹法检测VISTA抗体表达情况；构建小鼠移植瘤模型，游标卡尺测量溶瘤病毒治疗后瘤体大小的变化，且进行分析。结果 成功构建了携带免疫检查点VISTA抗体的溶瘤病毒HSV-1-ab-VISTA,和野生病毒相比，病毒增殖和裂解癌细胞的能力没有差别，HSV-1-ab-VISTA溶瘤病毒治疗显著缩小了小鼠的肿瘤大小。结论 HSV-1-ab-VISTA溶瘤病毒可抑制小鼠结直肠移植瘤的生长。     

溶瘤病毒联合其他药物用于肿瘤治疗的研究进展

溶瘤病毒作为一种抗肿瘤生物制剂,在肿瘤治疗中选择性地感染裂解肿瘤细胞,增加肿瘤抗原暴露,重塑肿瘤微环境,增加肿瘤微环境中免疫细胞浸润,激活免疫系统,发挥抗肿瘤作用.由于溶瘤病毒单药治疗效果不佳,而溶瘤病毒与其他抗癌药物联用的多个临床研究均表现出良好的抗肿瘤效果,联合用药有望释放溶瘤病毒疗法抗肿瘤方面的巨大潜能.本文从溶...     

溶瘤病毒药物非临床安全性评价的思考

溶瘤病毒药物(OVs)是一类新型的抗肿瘤生物药,是以结构改造型病毒为载体进行构建,选择性地感染肿瘤细胞并进行复制,溶解和破坏肿瘤组织,对正常组织不造成损伤.该类药物具有载体种类多样、携带外源基因片段广泛、抗肿瘤效果明显、临床可与多种药物联用的优点.溶瘤病毒药物同时属于基因治疗和生物技术药物范畴,对这类药物开展临床前安全...     

溶瘤病毒免疫治疗的研究进展

癌症已成为人类健康的严重威胁。目前传统肿瘤治疗方法对某些癌症效果不佳,而且严重影响患者的生活质量。随着肿瘤免疫疗法的兴起,溶瘤病毒作为一种新兴的抗肿瘤药物取得了巨大的研究进展,具有直接杀伤肿瘤细胞、激发机体免疫应答、增强其他抗肿瘤药物效果等多种功能,与传统治疗方法相比具有特异性强、副作用小、能抗多种类型肿瘤等优势。此文综述溶瘤病毒免疫治疗的作用机制,以及进一步研究的前景与挑战等。     

组蛋白去乙酰化酶抑制剂抗肿瘤临床研究进展

综述了近年来组蛋白去乙酰化酶(HDAC)抑制剂作为抗肿瘤药的临床研究进展。组蛋白去乙酰化酶抑制剂可以引导肿瘤细胞生长停滞、分化和凋亡,是很有前途的癌症治疗药物。目前,超过十多种组蛋白去乙酰化酶抑制剂作为治疗血液肿瘤和恶性实体瘤药物,有上百个临床试验正在进行中。     

国际治疗性肿瘤疫苗的开发与研究进展

肿瘤是全球人类第二大死因。一些肿瘤通常难以用像手术、放疗和化疗等常规治疗方法治疗,但可用肿瘤疫苗帮助刺激人体的免疫应答使其得到控制。将疫苗用于由诸如乙型肝炎病毒和人乳头瘤病毒(HPV)等致瘤病毒引起的感染现已非常成功地降低了这些感染导致的肿瘤发病率。治疗性肿瘤疫苗从免疫疗法兴起之初就给人们带来了很大的希望。尽管治疗性肿瘤疫苗在临床试验取得一些成功并有一种治疗前列腺肿瘤的疫苗获得批准,但大多数治疗性疫苗仍在临床试验之中。为了了解国际治疗性肿瘤疫苗的开发与研究现状,依据美国药物研究与生产商协会(PhRMA)最近发布的报告及临床试验数据库(Clinicaltrials.gov)与相关新药数据库中的数据,重点对进入Ⅲ期临床试验的3种抗原疫苗、3种肿瘤细胞疫苗、6种树突状细胞疫苗、5种核酸疫苗和2种其他治疗性肿瘤疫苗进行了分析和综述。分析结果表明,这19种肿瘤疫苗中许多在中期分析报告中,无论是在延长无复发生存率(RFS)和总生存率(OS)方面,还是在耐受性、安全性等方面,都显示出良好的开发前景。

     

溶瘤病毒的研究现状与临床进展

溶瘤病毒是一类可选择性感染并杀死肿瘤,但不影响正常细胞生长的天然或基因重组病毒。作为新型免疫疗法,溶瘤病毒已被证实具有激活抗肿瘤免疫应答、调节肿瘤微环境、增强免疫检查点抑制剂效力等作用。然而,溶瘤病毒疗法仍存在给药方式、抗病毒免疫反应、选择合适的受试者等挑战。简介溶瘤病毒药物载体及特征、溶瘤病毒的抗肿瘤机制及改造策略,综述临床研究中以溶瘤病毒为基础的各类联合疗法,并对溶瘤病毒亟待解决的挑战进行梳理。     

简讯

新型溶瘤病毒　　美国Ｏｎｙｘ制药公司公布了两种新的溶瘤病毒的资料。基因工程腺病毒Ｏｎｙｘ 0 1 5是公司第一代拳头产品 ,正在进行头、颈部癌症治疗的Ⅲ期试验和其他肿瘤的Ⅰ和Ⅱ期试验。第二代病毒掺入胞嘧啶脱氨酶基因 ,称为武装的治疗性病毒 (ＡＴＶ)。胞嘧啶脱氨酶把 5 氟胞嘧啶 ( 5 ＦＣ)转化为 5 氟尿嘧啶 ( 5 ＦＵ) ,后者是第一线化疗制剂。ＡＴＶ应能增加抗肿瘤应答强度和持久性 ;动物研究表明 ,在 5 ＦＣ存在的情况下 ,ＡＴＶ可增强抗肿瘤应答 ,且与肿瘤内高浓度 5 ＦＵ和全身性亚毒性水平相关。　　另一种新制品为Ｏｎｙｘ 4 …     

溶瘤病毒在肿瘤治疗中的研究进展

溶瘤病毒能特异性感染和裂解肿瘤细胞,且对正常细胞无损伤。其溶瘤特性和肿瘤靶向性在肿瘤治疗中的潜力值得关注。本文综述新城疫病毒、单纯疱疹病毒-1和溶瘤腺病毒治疗肿瘤的最新进展。     

二氯乙酸钠与肿瘤治疗的新进展

二氯乙酸钠(Sodiumdichloroacetate,DCA)是一种小分子化合物,多年来一直用于治疗乳酸酸中毒。近年来研究发现,DCA能作用于肿瘤细胞能量代谢途径,促进肿瘤细胞氧化磷酸化、诱导凋亡,抑制肿瘤生长;同时还发现DCA联合化疗、放疗、溶瘤病毒、DNA甲基化抑制剂、碳酸氢盐等其他治疗方法能进一步提高抗肿瘤疗效,为肿瘤治疗提供了新的策略。本文综述了DCA在抗肿瘤治疗中的作用、安全性以及在肿瘤治疗中的潜在应用价值的新进展。     

Oncolytic viruses for the treatment of malignant glioma

Malignant glioma is the most common primary malignancy of the human CNS. Despite decades of research, the current therapeutic strategy consists of a multimodal regimen of surgery, chemotherapy and radiation. This course of therapy yields a median survival after diagnosis of ～ 1 year. This dismal prognosis inspires the ongoing development of novel oncolytic agents targeting glioma, which include gene therapy, immunomodulatory therapy and oncolytic viruses. Oncolytic viruses are defined by their ability to target, replicate in and lyse tumour cells without critically damaging surrounding non-cancerous tissue. Although some viruses are naturally oncolytic and tumour-selective, the advent of modern recombinant DNA technology has allowed the engineering of additional viruses with improved therapeutic indices. This technological advance has enabled rapid growth in the field of viral therapy. Reovirus, Newcastle disease virus (NDV), measles virus, adenovirus, poliovirus and herpes simplex virus-1 are in preclinical and clinical development for use as oncolytic agents against malignant glioma. This report will focus on the recent patent literature in the field of oncolytic viruses for the treatment of malignant glioma.     

Radiovirotherapy: principles and prospects in oncology

Radiovirotherapy is defined as the use of viruses to deliver radioisotopic treatment into infected cells. Oncolytic viruses are able to selectively target and kill cancer cells. The combination of oncolytic viruses and radiation therapies can have synergistic antitumour properties. Viruses may act as radiosensitizers, and radiations can increase viral oncolytic properties. The combination of oncolytic viruses with a virally-directed radioisotope therapy is an innovative method to combine viruses and radiation therapy, selectively within the tumour cells. The sodium/iodide symporter (NIS) is the main transgene that has been studied for this approach. NIS can mediate the uptake of isotopes of iodine and technetium 99m for in vivo gene expression imaging and therapy. This review highlights the principles of radiovirotherapy, and its recent progress. Better understanding of the regulation of NIS opens up pathways by which to potentiate the functional expression of NIS. In terms of the therapeutic isotope, Iodine-131 has been most frequently studied but other isotopes (astatine- 211, rhenium-188) are of growing interest. Oncolytic viruses are able to infect selectively and replicate in cancer cells and promising early phase clinical trials have been recently published. Their development allows a better selectivity of viral infection and adds a virus-specific cytotoxicity to the therapeutic approach. Active research into strategies such as immunosuppressive treatment and cell-based carrier systems is seeking to circumvent the host antiviral immune response and, thus, increase the potential for systemic delivery. Finally, other anticancer therapies such as chemotherapy and external beam radiotherapy may have a synergistic effect with radiovirotherapy and such combinatorial approaches offering the prospect of accelerated translation into clinical studies.     

ONCOLYTIC HERPES SIMPLEX VIRUS 1 (HSV-1) VECTORS: INCREASING TREATMENT EFFICACY AND RANGE THROUGH STRATEGIC VIRUS DESIGN

Viruses have long been considered potential anticancer treatments. Wild-type viruses have been tested as anticancer agents in clinical trials since the 1960s. The possibility of viral oncolysis as an alternate cancer therapy was transformed by the emergence of modern genetic engineering. The herpes simplex virus (HSV) family offers particular advantages for use as a viral oncolytic. The engineered vectors that make up oncolytic HSVs (oHSVs) have demonstrated remarkable safety in clinical trials, with some evidence of efficacy. The past decade has seen a focus on increasing the efficacy of oncolytic vectors by adding exogenous transgenes to enhance tumor destruction. The current paper describes the various strategies for engineering HSV for increased cancer tissue specificity and efficacy. Presented are the rationale, preclinical data and clinical data where available. This is meant to illustrate a basic framework for the development of a novel therapy meant to exploit the viral life cycle for the killing of cancer.     

From ONYX-015 to armed vaccinia viruses: the education and evolution of oncolytic virus development

The current field of oncolytic virus development has evolved from, and been educated by, the route adenoviruses have taken to Phase III development in the United States (Onyx-015) and commercial approval in China (H101). Clinical development of these E1B-deleted viruses showed that a staged approach, from single-agent intratumoral injections to trials testing intravenous delivery and trials in combination with approved therapies is judicious and can be successful. Additional oncolytic products are in development, including andenovirus plus other promising platforms such as herpes simplex virus, Newcastle disease virus, reovirus and vaccinia virus. These second-generation products seek to expand clinical utility beyond the modest local efficacy of Onyx-015/H101 to potent systemic delivery and efficacy. Improvement of efficacy in metastatic cancer will depend not only on enhanced killing of tumor cells, but also on achieving intravenous delivery and better intratumoral dissemination. Many viruses inherently replicate preferentially in tumors, and engineering can increase this therapeutic index by targeting genetic features of cancers. However, both viruses and cancer cells have complex biologies. Therefore, research may reveal that there is not a single predictive factor for tumor specificity. For example, the Onyx-015 mechanism-of-selectivity has proved to be complex. Further research regarding pathway dependence for other oncolytic viruses may also reveal multiple influences on their tumor tropism.     

Regulatory aspects of oncolytic virus products

Many types of oncolytic viruses, wild-type virus, attenuated viruses and genetically-modified viruses, have been developed as an innovative cancer therapy. The strategies, nature, and technologies of oncolytic virus products are different from the conventional gene therapy products or cancer therapy products. From the regulatory aspects to ensure the safety, efficacy and quality of oncolytic viruses, there are several major points during the development, manufacturing, characterization, non-clinical study and clinical study of oncolytic viruses. The major issues include 1) virus design (wild-type, attenuated, and genetically engineered strains), 2) poof of concept in development of oncolytic virus products, 3) selectivity of oncolytic virus replication and targeting to cancer cells, 4) relevant animal models in non-clinical studies, 5) clinical safety, 6) evaluation of virus shedding. Until now, the accumulation of the information about oncolytic viruses is not enough, it may require the unique approach to ensure the safety and the development of new technology to characterize oncolytic viruses.     

Recent clinical experience with oncolytic viruses

There has been interest in using viruses to treat cancer for over a century. Recent clinical efforts, driven on by significant preclinical advances, have focussed on the safety of using replication-competent viruses. Recently published clinical trials of six oncolytic viruses (adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia) have added to the accumulating data that endorse oncolytic viruses as a safe and well tolerated treatment approach. Conclusive evidence of efficacy remains to be demonstrated, but randomised clinical trials are now underway.     

Targeted and armed oncolytic poxviruses for cancer: the lead example of JX-594

Oncolytic viruses (OVs) are designed to replicate in, and subsequently lyse cancer cells. Numerous oncolytic virus platforms are currently in development. Here we review preclinical and clinical experience with JX-594, the lead candidate from the targeted and armed oncolytic poxvirus class. JX-594 is derived from a vaccinia vaccine strain that has been engineered for 1) enhanced cancer targeting and 2) has been "armed" with the therapeutic transgene granulocytemacrophage colony stimulating factor (GM-CSF) to stimulate anti-tumoral immunity. Poxviruses have many ideal features for use as oncolytic agents. The development of oncolytic vaccinia viruses is supported by a large safety database accumulated in the smallpox eradication program. In addition, poxviruses have evolved unique capabilities for systemic spread through the blood that can be harnessed for the treatment of metastatic disease. JX-594 demonstrates a high degree of cancer selectivity and systemic efficacy by multiple mechanisms-of-action (MOAs) in preclinical testing. Data from Phase 1 and 2 clinical trials has confirmed that these features result in potent and systemic efficacy in patients with treatment refractory metastatic cancers.