间充质干细胞作为溶瘤病毒细胞载体的研究进展

溶瘤病毒能够在肿瘤细胞内大量增殖并最终裂解肿瘤细胞,同时还具有对肿瘤微环境的调控作用,激发宿主抗肿瘤免疫反应。但是溶瘤病毒经静脉注射后引发的机体抗病毒免疫应答以及溶瘤病毒的肿瘤靶向性差,使得临床上对肿瘤的疗效不佳。间充质干细胞具有肿瘤趋向性、免疫抑制功能和旁分泌效应。间充质干细胞运载溶瘤病毒既可以保护病毒不被免疫系统清除又可精准将病毒递送到肿瘤病变部位,同时病毒感染可改变间充质干细胞分泌的细胞因子谱,促进机体抗肿瘤免疫反应。因此,间充质干细胞运载溶瘤病毒是治疗复发/难治性实体肿瘤的理想选择。本文结合临床前及临床研究的有关进展,对间充质干细胞运载溶瘤病毒治疗实体肿瘤进行综述,为间充质干细胞运载溶瘤病毒的临床应用提供了理论依据。     

细胞荷载溶瘤病毒

溶瘤病毒是一类仅在肿瘤细胞内特异增殖的新型病毒载体,具有高度的肿瘤靶向性和良好的转染率.局部注射溶瘤病毒治疗体表肿瘤已获得显著疗效,但全身应用后机体的免疫防御机制明显限制了溶瘤病毒的治疗效果.细胞荷载溶瘤病毒可能是克服这一瓶颈的有效策略,为治疗肿瘤提供了新的平台.     

溶瘤病毒治疗肿瘤研究进展

溶瘤病毒通过病毒复制导致肿瘤细胞裂解。溶瘤病毒用于肿瘤的治疗已经有近60年的历史,已有大量研究对病毒的改造、给药途径探索、疗效观察、机制及危险性等方面进行了广泛探讨,对溶瘤病毒的认识有了很大进展,溶瘤病毒有望成为治疗肿瘤的重要武器。现综述溶瘤病毒发展、分类及其溶瘤机制,并分析溶瘤病毒在肿瘤治疗中的优缺点和研究现状。     

溶瘤病毒治疗肿瘤研究进展

溶瘤病毒通过病毒复制导致肿瘤细胞裂解。溶瘤病毒用于肿瘤的治疗已经有近60年的历史,已有大量研究对病毒的改造、给药途径探索、疗效观察、机制及危险性等方面进行了广泛探讨,对溶瘤病毒的认识有了很大进展,溶瘤病毒有望成为治疗肿瘤的重要武器。现综述溶瘤病毒发展、分类及其溶瘤机制,并分析溶瘤病毒在肿瘤治疗中的优缺点和研究现状。     

细胞荷载溶瘤病毒治疗肿瘤的研究进展

静脉注射的溶瘤病毒可被免疫系统完全排除而不能发挥其抗肿瘤作用。研究表明,溶瘤病毒用细胞包装后可以有效避免病毒被机体免疫系统清除,同时,病毒和载体细胞的生物学活性不受影响;另外采用具有肿瘤细胞、肿瘤基质或肿瘤解剖定位靶向性的细胞载体,可以将病毒准确地输送至肿瘤病灶,有效发挥溶瘤病毒的抗肿瘤效应。本文将对细胞荷载溶瘤病毒治疗肿瘤方面的研究进展做一综述。     

溶瘤病毒——新城疫病毒研究进展

新城疫病毒(NDV)能选择性杀伤人及动物肿瘤细胞,体内外实验证实新城疫病毒(NDV)对多种人类肿瘤细胞具有杀伤作用.作用机制包括选择性在肿瘤细胞内复制,直接导致肿瘤细胞溶解;通过线粒体途径等诱导肿瘤细胞凋亡,促进细胞因子产生,提高肿瘤免疫原性等,近几年临床研究取得了令人鼓舞的结果.     

溶瘤病毒治疗乳腺癌的研究进展

根据国际癌症研究机构（International Agency for Research on Cancer,IARC）2011年最新报告,乳腺癌是妇女发病率最高的恶性肿瘤,严重威胁着女性的生命健康。尽管目前治疗效果已有较大改善,但是病灶一旦复发或者远处转移,传统治疗方法只能起到缓解病情的作用,并不能从根本上治疗患者,因此,临床上需要研究更有效的方法以取代或辅助现有的传统治疗方法,从而治疗或缓解乳腺癌患者的临床症状。     

溶瘤病毒疗法的研究现状与展望

针对癌症的传统治疗手段主要有手术治疗、化疗、放疗等。这些方法虽然能在一定程度上控制肿瘤生长,但也存在一定的技术局限性。溶瘤病毒疗法作为一种新型的肿瘤细胞生物疗法,为恶性肿瘤的治疗带来了新的发展希望。溶瘤病毒能够在不影响正常细胞的情况下,发挥较强的肿瘤抑制和杀伤作用,同时通过免疫诱导促使机体产生抗肿瘤免疫反应,进一步提高对肿瘤细胞的杀伤效果。然而,由于病毒自身存在较强的免疫原性,静脉注射后会引发机体产生不同程度的免疫应答,并且溶瘤病毒的肿瘤靶向性和单独治疗能力有限,使得其最终的肿瘤治疗效果并不理想。研究者通过设计并构建不同类型的载体来装载病毒,以封闭其固有的免疫原性,延长其血液循环时间的同时,进一步提高其对恶性肿瘤的靶向性,并在此基础上将溶瘤病毒与其他肿瘤治疗手段结合,进而增强溶瘤病毒的肿瘤治疗效果。本文将重点围绕如何有效构建溶瘤病毒载体及联合其他肿瘤治疗手段以提高溶瘤病毒的肿瘤治疗效果,对近期相关研究进展进行综述介绍。     

溶瘤病毒治疗恶性肿瘤研究进展

据统计,约l5%的人类肿瘤与病毒感染有关.一些病毒可通过表达蛋白或携带遗传调控元件,干扰正常细胞生长周期,导致细胞转化和肿瘤发生;另一方面,许多病毒又可特异性地感染肿瘤细胞并在细胞内复制,杀伤肿瘤细胞,这类病毒称为溶瘤病毒(oncolytic virus,OV).溶瘤病毒能够选择性地在肿瘤细胞中复制,造成细胞病理效应和机体免疫反应,导致肿瘤细胞的裂解死亡,同时对正常细胞和组织却没有破坏作用或影响较小.     

免疫增强性溶瘤病毒肿瘤疫苗的研究进展

溶瘤病毒可在肿瘤细胞中增殖复制,并溶解瘤细胞,释放肿瘤抗原,激发机体自身的抗肿瘤免疫反应,它具有基因操控性、规模化、肿瘤选择性等生物学特征,从而成为个性化肿瘤疫苗的优良载体。但是,肿瘤存在很强的免疫抑制网络,单纯性溶瘤病毒难以激发理想的免疫应答。因此,根据需要加载不同的免疫调控分子,以增强机体的抗肿瘤免疫能力,已成为溶瘤病毒肿瘤疫苗研究的新思路。基于这一原理设计的OncoVexGM-CSF、JX-594、CG0070、KH901等免疫增强型肿瘤疫苗在临床试验中取得了较为显著的疗效,为肿瘤个性化疫苗的临床应用带来了曙光。尽管如此,溶瘤病毒肿瘤疫苗在疗效评价标准、作用机制、给药方式与治疗方案等方面还需要更为深入的探索。     

Future directions: oncolytic viruses

Oncolytic viruses offer a promising new modality for cancer treatment. The strategy of this therapy is to develop viruses capable of selectively infecting and replicating in malignant tumor cells. Oncolytic viruses can spread and destroy malignant tumors without deleterious effects in normal tissues. These viruses are genetically engineered based on both the biology of replicating viruses and the major genetic defects in human cancer cells, so that they can replicate in cancer cells but not in normal cells. The key to the development of such viruses is the identification of viral genes, the deletion or modification of which enables tumor-specific cell destruction. Several clinical trials have demonstrated the safety of oncolytic viruses as cancer therapy and have also shown some encouraging results. Much evidence suggests that oncolytic viral therapy works in synergy with standard cancer therapies. In this review, we will focus on the oncolytic viruses that may be beneficial to patients with lung cancer in the near future.     

Recent progress in the battle between oncolytic viruses and tumours

In the past 5 years, the field of oncolytic virus research has matured significantly and is moving past the stage of being a laboratory novelty into a new era of preclinical and clinical trials. What have recent anticancer trials of oncolytic viruses taught us about this exciting new line of therapeutics?     

Cancer treatment involving oncolytic viruses

Viruses capable of inducing lysis of malignant cells through their replication process are known as "oncolytic" viruses. Clinical trials in oncology have been performed with oncolytic viruses for nearly fifty years. Both systemic and intratumoral routes of administration have been explored. Toxicity has generally been limited to injection site pain, transient fever, and tumor necrosis. Responses with early crude materials were usually short in duration; however, recent trials with gene-attenuated viruses suggest a more prolonged duration of responses.     

Progress of oncolytic viruses in sarcomas

Oncolytic virotherapy has shown exciting promise for the treatment of many types of solid tumors. Pediatric sarcomas are an aggressive type of pediatric malignancy known to show limited responsiveness to current therapies, leading to unacceptably high morbidity and mortality. Oncolytic viruses have only recently been used for the treatment of this challenging cancer, and results have been encouraging. Five clinical trials are currently open evaluating the use of oncolytic viruses in pediatric malignancies. Advances in genetic engineering of the viruses include improving the ability of the virus to infect tumor cells, engineering the virus with transgenes which improve the virus' ability to kill tumor cells and manipulating the virus to enhance concomitantly administered therapies. Further understanding of the antiviral immune response and a viral induced anti-tumor immune response will permit a maximization of oncolytic virotherapy.     

Armed therapeutic viruses: strategies and challenges to arming oncolytic viruses with therapeutic genes

Oncolytic viruses are attractive therapeutics for cancer because they selectively amplify, through replication and spread, the input dose of virus in the target tumor. To date, clinical trials have demonstrated marked safety but have not realized their theoretical efficacy potential. In this review, we consider the potential of armed therapeutic viruses, whose lytic potential is enhanced by genetically engineered therapeutic transgene expression from the virus, as potential vehicles to increase the potency of these agents. Several classes of therapeutic genes are outlined, and potential synergies and hurdles to their delivery from replicating viruses are discussed.     

Reovirus and other oncolytic viruses for the targeted treatment of cancer

In the last 50 years, there have been a number of anecdotal reports of viral infections causing transient cancer remissions in patients with advanced disease. However, during the last decade, these reports have been supplemented by data indicating the potential antitumor effect of a number of viruses. As a consequence, there has been increasing interest in the development of oncolytic viruses—viruses that selectively destroy cancer cells—as cancer therapeutics. They can be divided into two groups: natural tumor-selective wild-type viruses and genetically engineered tumor-selective viruses; both present advantages and disadvantages. The use of oncolytic viruses as anticancer agents still represents a major challenge and many obstacles need to be overcome: issues of systemic toxicity, tumor selectivity, immune response, and manufacture are added to the inconvenience of genetic manipulation. Reovirus is an inherently selective wild-type virus that seems to fulfill many of the above criteria for an oncolytic virus. Reovirus selectively replicates in Ras-activated cells and has been shown to possess antitumor activity both in vitro and in vivo. Since many tumors have an activated Ras pathway, the potential for using reovirus as an effective anticancer agent is substantial. Ongoing studies have demonstrated its safety when administered to cancer patients.     

Replication-selective oncolytic viruses in the treatment of cancer

In the search for novel strategies, oncolytic virotherapy has recently emerged as a viable approach to specifically kill tumor cells. Unlike conventional gene therapy, it uses replication competent viruses that are able to spread through tumor tissue by virtue of viral replication and concomitant cell lysis. Recent advances in molecular biology have allowed the design of several genetically modified viruses, such as adenovirus and herpes simplex virus that specifically replicate in, and kill tumor cells. On the other hand, viruses with intrinsic oncolytic capacity are also being evaluated for therapeutic purposes. In this review, an overview is given of the general mechanisms and genetic modifications by which these viruses achieve tumor cell-specific replication and antitumor efficacy. However, although generally the oncolytic efficacy of these approaches has been demonstrated in preclinical studies the therapeutic efficacy in clinical trails is still not optimal. Therefore, strategies are evaluated that could further enhance the oncolytic potential of conditionally replicating viruses. In this respect, the use of tumor-selective viruses in conjunction with other standard therapies seems most promising. However, still several hurdles regarding clinical limitations and safety issues should be overcome before this mode of therapy can become of clinical relevance.