An oncolytic herpes simplex virus vector, G47Δ, synergizes with paclitaxel in the treatment of breast cancer
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Fo r ove r o n e h u n d re d ye a r s , v i r u s e s h ave b e e n recognized as capable of killing tumor cells.At present, people are still researching and constructing more suitable oncolytic viruses for treating different malignant tumors.Although extensive studies have demonstrated that herpes simplex virus type 1 (HSV-1) is the most potential oncolytic virus, therapies based on herpes simplex virus type 1 vectors still arouse bio-safety and risk management issues.Researchers have therefore introduced the new idea of treating cancer with HSV-1 mutants labeled with radionuclides, combining radionuclide and oncolytic virus therapies.This overview briefly summarizes the status and mechanisms by which oncolytic viruses kill tumor cells, discusses the application of HSV-1 and HSV-1 derived vectors for tumor therapy, and demonstrates the feasibility and prospect of HSV-1 mutants labeled with radionuclides for treating tumors.
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The use of oncolytic herpes simplex virus type 1 (HSV-1) is a promising strategy for cancer treatment. Accumulating evidence indicates that, aside from the extent of replication capability within the tumor, the efficacy of an oncolytic HSV-1 depends on the extent of induction of host antitumor immune responses. Ways to modify the host immune responses toward viral oncolysis include expression of immunostimulatory molecules using oncolytic HSV-1 as a vector and co-administration of reagents that modulate immune reactions. Viral propagation may be enhanced via temporary suppression of innate immune responses. Elucidation of the role of the host immune system in oncolytic HSV-1 therapy is the key to establishing the approach as a useful clinical means for cancer treatment. Keywords: Herpes simplex virus type 1, oncolytic virus therapy, antitumor immunity, cancer immunotherapy, innate immunity
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Oncolytic virus (OV) is a kind of virus that can preferentially infect and kill tumor cells. The second oncolytic virus drug was oncolytic herpes simplex virus (oHSV) Talimogene Laherparepvec (T-VEC). HSV-1 infectious cell culture protein 34.5 (ICP34.5) and latency-associated transcript (LAT) genes are closely related to virus selective infection and latent infection. Their engineering is essential for constructing efficient and safe oHSV. We summarized the mechanisms of ICP34.5 and LAT in the course of HSV-1 infection and reviewed the engineered oHSVs. We are aimed to provide an insight in developing oHSV in the future.
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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.
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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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Oncolytic virus therapy has recently been recognized as a promising new treatment option for cancer. The strategy is to use genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells, without harming normal cells. Herpes simplex virus type 1 (HSV-1) has been well studied and has many advantages for the use in cancer therapy, making it the mainstay of current clinical trials of oncolytic virus therapy. Numerous preclinical and clinical studies of oncolytic HSV-1 have demonstrated its safety and antitumor efficacy, the latter of which is mainly attributable to its direct cytocidal effect. However, recent studies have also suggested that oncolytic HSV-1 elicits host antitumor immunity and induces immunogenic cancer cell death, thus offering possibilities for multifaceted strategies by focusing on enhancement of host anticancer immunity. In this review, we summarize the history and current status of preclinical and clinical studies of oncolytic virus therapy using HSV-1. Keywords: Clinical trial, G47Δ, genetically engineered, herpes simplex virus, HSV-1, oncolytic virus.
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