Incorporation of the B18R Gene of Vaccinia Virus Into an Oncolytic Herpes Simplex Virus Improves Antitumor Activity
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Interferon (IFN) antiviral defense mechanism plays a critical role in controlling virus infection. It thus represents a formidable hurdle for virotherapy. Despite the reported ability of herpes simplex virus (HSV) to counteract this defense, the duration and extent of HSV infection in vivo is still largely dictated by host's IFN activity status. Because the HSV genes that have been reported to block IFN activity mainly act intracellularly, we hypothesized that their inhibitory effect could be enhanced by exploiting a gene whose product acts extracellularly. The B18R gene from vaccinia virus encodes a secreted decoy receptor with a broad antagonizing effect against type I IFNs. We therefore cloned B18R into an HSV-1-based oncolytic virus to generate Synco-B18R. In the presence of increased IFN levels in vitro, Synco-B18R largely retained its oncolytic effect, whereas the tumor-killing ability of the parental virus, Synco-2D, was severely compromised. When injected intratumorally in vivo, Synco-B18R showed significantly greater oncolytic activity than Synco-2D. Our results suggest that incorporation of the vaccinia virus B18R gene can safely potentiate the antitumor effect of an oncolytic HSV, and that similar strategies may be useful with other types of oncolytic viruses.Keywords:
Virotherapy
Oncolytic virus can selectively kill cancer cells and normal cells are generally left intact.Nearly 10 kinds of oncolytic viruses have been developed in recent years.Vaccinia virus has an enormous use in humans for the eradication of smallpox.In addition,vaccinia virus replicates rapidly,has highly immunogenic and well-known side effect.Genetic modified vaccinia virus can selectively replicate and lyse tumor cells.The report ed oncolytic vaccinia virus researches mainly based on the backbone of Western Reverse strain,Wyeth strain,List er strain and Copenhagen strain.There is no related report about Tian-Tan strain.
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Treating tumors with viruses, that is, oncolytic viruses, was originally suggested by the clinicians who witnessed tumor regression after spontaneous viral infections. An increased understanding of virology, as well as experience using viruses in cancer gene therapy, has prompted a new wave of oncolytic virotherapy. The use of virotherapy against neuroblastoma (NB) is an emerging field. The use of oncolytic adenoviruses in the clinic has been recently reported in sporadic cases of children with metastatic NB. Oncolytic adenovirus (ICOVIR-5) is used for treating four children with refractory metastatic NB, using mesenchymal stem cells (MSCs) as the carrier for our oncolytic adenovirus. In the cases of oncolytic viruses, carrier cells can also protect the virus from inactivation by immune defense mechanisms. Cells can also serve as production factories to produce and correctly process these agents in their most physiological form.
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Destruction of the tumor (cancerous) cells may be caused by live viruses, which have replicative ability and replicate selectively in tumor cells, known as oncolytic virotherapy. In comparison of conservative cancer therapy, tumor-selective replicating viruses have more advantages. These viruses have introduced new methodologies for the human cancer treatment. Numerous strategies are used in development of virotherapeutics. Virotherapy is not unusual concept, but modern advances in technology of genetic modification of oncolytic viruses have improved the ability of targeting tumor cells more specifically, it triggered the development of novel ammunition to fight cancer. An effective virotherapeutic approach with oncolytic viruses exhibits the feasibility and safety under clinical approach. New strategies are being explored to overcome basic obstacles and challenges in virotherapy. Administration of oncolytic viruses, logically, will successfully augment new treatments against many kinds of tumors. Some encouraging antitumor responses shown by combination therapy are provoking strong immunity against established cancer. Chief developments in oncolytic virotherapy have seen in past several years. Significant understandings have been provided by findings on the interface among immune comebacks and viruses, whereas potential results have shown in clinical trials.
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Future directions for the field of oncolytic virotherapy: a perspective on the use of vaccinia virus
Oncolytic virotherapy is an emerging biotherapeutic platform based on genetic engineering of viruses capable of selectively infecting and replicating within cancer cells. Such viruses have been found to be both safe and to produce antitumour effects in a number of Phase I and II clinical trials. Early work in this field has been pioneered with strains of adenovirus which, although well suited to gene therapy approaches, have displayed certain limitations in their ability to directly destroy and spread through tumour tissues, particularly after systemic administration. Investigators have subsequently been examining the feasibility of using a variety of different viruses as oncolytic agents. Vaccinia virus is perhaps the most widely administered and successful medical product in history; it displays many of the qualities thought necessary for an effective antitumour agent and is particularly well characterised in people due to its role in the eradication of smallpox. Vaccinia has a short life cycle and rapid spread, strong lytic ability, inherent systemic tumour targeting, a large cloning capacity and well-defined molecular biology. In addition, the virus produces no known disease in humans, has been delivered safely to millions of people and has already demonstrated antitumoural efficacy in trials with vaccine strains. These qualities, along with strategies for further improving the safety and antitumour effectiveness of vaccinia, will be discussed in relation to the broad spectrum of clinical experience already achieved with this virus in cancer therapy.
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Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.
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Interferon (IFN) antiviral defense mechanism plays a critical role in controlling virus infection. It thus represents a formidable hurdle for virotherapy. Despite the reported ability of herpes simplex virus (HSV) to counteract this defense, the duration and extent of HSV infection in vivo is still largely dictated by host's IFN activity status. Because the HSV genes that have been reported to block IFN activity mainly act intracellularly, we hypothesized that their inhibitory effect could be enhanced by exploiting a gene whose product acts extracellularly. The B18R gene from vaccinia virus encodes a secreted decoy receptor with a broad antagonizing effect against type I IFNs. We therefore cloned B18R into an HSV-1-based oncolytic virus to generate Synco-B18R. In the presence of increased IFN levels in vitro, Synco-B18R largely retained its oncolytic effect, whereas the tumor-killing ability of the parental virus, Synco-2D, was severely compromised. When injected intratumorally in vivo, Synco-B18R showed significantly greater oncolytic activity than Synco-2D. Our results suggest that incorporation of the vaccinia virus B18R gene can safely potentiate the antitumor effect of an oncolytic HSV, and that similar strategies may be useful with other types of oncolytic viruses.
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Vaccinia virus (VACV) has been widely used in humans for the eradication of smallpox. Since its natural ability of selective infection and replication in tumor cells without harming the normal tissue, VACV becomes a promising candidate in cancer therapy. In recent years, a variety of strategies have been successfully applied to further enhance the tumor selectivity and anti-tumor efficacy of VACV. These engineered VACVs, such as JX-594, have shown promising results in cancer treatment and have made remarkable progress in clinical trials. This review first briefly introduces the oncolytic VACV, and then focuses on the strategies applied in VACV engineering. We also discuss the main challenges and the future directions in the development of oncolytic VACV.
Key words:
Vaccinia virus; Oncolytic virus; Virus modification; Tumor treatment; Clinical trial
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Smallpox vaccine
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Oncolytic viruses, which may be naturally occurring or genetically engineered, are a type of virus that infects and destroy cancer cells preferentially. Owing to their selectivity, they outperform conventional chemotherapy and radiotherapy, which both have a tendency to impact non-target cells and cause unwanted adverse side effects. Oncolytic virotherapy is a type of cancer treatment in which oncolytic viruses are deliberately introduced into patients affected with cancers in order for them to infect and destroy cancer cells locally or systemically, in a manner analogous to chemotherapy but with a greater degree of selectivity. Multiple studies indicate that oncolytic virotherapy is effective in vitro but in vivo findings remain ambiguous due to the approach's primary limitation: inefficient therapeutic agent delivery to its target, which is heavily influenced by the immune system. Here, we propose overcoming this limitation by exploiting a recent discovery in cancer research: a carrier cell. By exploiting their tumor-promoting activities, mesenchymal stem cells may be employed for cancer therapy by serving as a carrier for the oncolytic viruses toward their target. This approach directly addresses the limitation of conventional oncolytic virotherapy, where oncolytic viruses are often poorly delivered after systemic administration.
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