Effect Of Virotherapy Research Articles

Efficacy of Different Oncolytic Vaccinia Virus Strains for the Treatment of Murine Peritoneal Mesothelioma.

Effective treatment options for peritoneal surface malignancies (PSMs) are scarce. Oncolytic virotherapy with recombinant vaccinia viruses might constitute a novel treatment option for PSM. We aimed to identify the most effective oncolytic vaccinia virus strain in two murine mesothelioma cell lines and the oncolytic potential in a murine model of peritoneal mesothelioma. Cell lines AB12 and AC29 were infected in vitro with vaccinia virus strains Lister (GLV-1h254), Western Reserve (GLV-0b347), and Copenhagen (GLV-4h463). The virus strain GLV-0b347 was shown most effective in vitro and was further investigated by intraperitoneal (i.p.) application to AB12 and AC29 mesothelioma-bearing mice. Feasibility, safety, and effectiveness of virotherapy were assessed by evaluating the peritoneal cancer index (PCI), virus detection in tumor tissues and ascites, virus growth curves, and comparison of overall survival. After i.p. injection of GLV-0b347, virus was detected in both tumor cells and ascites. In comparison to mock-treated mice, overall survival was significantly prolonged, ascites was less frequent and PCI values declined. However, effective treatment was only observed in animals with limited tumor burden at the time point of virus application. Nonetheless, intraperitoneal virotherapy with GLV-0b347 might constitute a novel therapeutic option for the treatment of peritoneal mesothelioma. Additional treatment modifications and combinational regimes will be investigated to further enhance treatment efficacy.

The Effect of Virotherapy, Chemotherapy, and Immunotherapy to Immune System: Mathematical Modelling Approach

Medical research and therapeutic interventions continue to evolve, and one interesting area of study is the complex interaction among virotherapy, chemotherapy, and the immune system. Each treatment has its own advantages and disadvantages. In this study, a mathematical model was developed to describe how the immune system, tumor cells, and normal cells interact when all three types of therapy are used to treat cancer patients. To determine the effectiveness of various treatments, numerical simulations of eight different treatment strategies were performed. These simulations measured how much the concentration of immune cells, tumor cells, and normal cells decreased as a result of the treatment. Based on the numerical simulations performed, the application of the three types of therapy provided the greatest reduction (99%) in the concentration of tumour cells but also provided a significant reduction (68%) in the concentration of immune cells in the body.

Analysis and analytical simulation for a biophysical fractional diffusive cancer model with virotherapy using the Caputo operator

<abstract> <p>In this paper, a biophysical fractional diffusive cancer model with virotherapy is thoroughly analyzed and analytically simulated. The goal of this biophysical model is to represent both the dynamics of cancer development and the results of virotherapy, which uses viruses to target and destroy cancer cells. The Caputo sense is applied to the fractional derivatives. We look at the governing model's existence and uniqueness. For analytical solutions, the Laplace residual power series approach is used. The study investigates the model's dynamic behavior, shedding light on the development of cancer and the effects of virotherapy. The research advances our knowledge of cancer modeling and treatment options. Numerical simulations show the agreement between the analytical results and the related numerical solutions, proving the usefulness of the analytical solution.</p> </abstract>

Analysis of Immunological Treatment Effects of Virotherapy in Tumor Tissue.

In addition of being directly tumoricidal, oncolytic viruses have emerged as potent partners for established and investigational immunotherapies due to their immune-stimulatory effects. The shifting focus on virus-mediated immune modulation calls for a comprehensive analysis of the tumor microenvironment (TME) and the factors orchestrating the antiviral and antitumor immune response. The oncolytic VSV-GP studied in our lab is a safe and potent antitumor agent with a fast replication cycle and killing of a broad range of different cancer types. It induces a robust local inflammatory conversion of the TME and drives a strong adaptive immune response toward the tumor. Here we present our multidisciplinary approach to study VSV-GP treatment effects in tumors by assessing both immune cells (tumor-infiltrating lymphocytes and tumor-associated macrophages) and immune-regulatory factors (cytokines) as well as characterizing immune signatures using an immune-targeted NanoString gene expression system.

SIRT1 Modulates the Sensitivity of Prostate Cancer Cells to Vesicular Stomatitis Virus Oncolysis.

Oncolytic virotherapy represents a promising experimental anticancer strategy, based on the use of genetically modified viruses to selectively infect and kill cancer cells. Vesicular stomatitis virus (VSV) is a prototypic oncolytic virus (OV) that induces cancer cell death through activation of the apoptotic pathway, although intrinsic resistance to oncolysis is found in some cell lines and many primary tumors, as a consequence of residual innate immunity to the virus. In the effort to improve OV therapeutic efficacy, we previously demonstrated that different agents, including histone deacetylase inhibitors (HDIs), functioned as reversible chemical switches to dampen the innate antiviral response and improve the susceptibility of resistant cancer cells to VSV infection. In the present study, we demonstrated that the NAD+-dependent histone deacetylase SIRT1 (silent mating type information regulation 2 homolog 1) plays a key role in the permissivity of prostate cancer PC-3 cells to VSVΔM51 replication and oncolysis. HDI-mediated enhancement of VSVΔM51 infection and cancer cell killing directly correlated with a decrease of SIRT1 expression. Furthermore, pharmacological inhibition as well as silencing of SIRT1 by small interfering RNA (siRNA) was sufficient to sensitize PC-3 cells to VSVΔM51 infection, resulting in augmentation of virus replication and spread. Mechanistically, HDIs such as suberoylanilide hydroxamic acid (SAHA; Vorinostat) and resminostat upregulated the microRNA miR-34a that regulated the level of SIRT1. Taken together, our findings identify SIRT1 as a viral restriction factor that limits VSVΔM51 infection and oncolysis in prostate cancer cells.IMPORTANCE The use of nonpathogenic viruses to target and kill cancer cells is a promising strategy in cancer therapy. However, many types of human cancer are resistant to the oncolytic (cancer-killing) effects of virotherapy. In this study, we identify a host cellular protein, SIRT1, that contributes to the sensitivity of prostate cancer cells to infection by a prototypical oncolytic virus. Knockout of SIRT1 activity increases the sensitivity of prostate cancer cells to virus-mediated killing. At the molecular level, SIRT1 is controlled by a small microRNA termed miR-34a. Altogether, SIRT1 and/or miR-34a levels may serve as predictors of response to oncolytic-virus therapy.

Combination of virotherapy with VSV and tumor vaccination significantly enhances the efficacy of antitumor therapy.

Oncolytic virotherapy offers the potential to treat tumors both as asingle agent and in combination with conventional therapies such as chemotherapy and immunological therapy. Here, we describe an effective treatment regimen which combines virotherapy with immunotherapy. IFN-α and co-stimulator IL-2 along with tumor cell lysate vaccination with intratumoral administration of oncolytic vesicular stomatitis virus (VSV) resulted in regression of established TC1 papilloma tumor model in C57BL/6 mice. The remarkable results especially in the group receiving tumor vaccination and virotherapy together (TC1-VSV) were obtained. Combination therapy synergistically enhanced CTL activity against tumor cells and reduced tumor size, although significant reduction in tumor size was observed in both groups receiving VSV or tumor vaccine alone. The presented data suggest that the effectiveness of virotherapy is enhanced when combined with immunotherapy by priming specific CD8 Tcells against tumor antigens through tumor vaccination and boosting by exposure of antigens upon virus infection. Keywords: virotherapy; VSV; tumor vaccine; immunotherapy; IFN-α; IL-2.

Combined therapy of oncolytic adenovirus and temozolomide enhances lung cancer virotherapy in vitro and in vivo

Oncolytic adenoviruses (OAds) are very promising for the treatment of lung cancer. However, OAd-based monotherapeutics have not been effective during clinical trials. Therefore, the effectiveness of virotherapy must be enhanced by combining OAds with other therapies. In this study, the therapeutic potential of OAd in combination with temozolomide (TMZ) was evaluated in lung cancer cells in vitro and in vivo. The combination of OAd and TMZ therapy synergistically enhanced cancer cell death; this enhanced cancer cell death may be explained via three related mechanisms: apoptosis, virus replication, and autophagy. Autophagy inhibition partially protected cancer cells from this combined therapy. This combination significantly suppressed the growth of subcutaneous H441 lung cancer xenograft tumors in athymic nude mice. In this study, we have provided an experimental rationale to test OAds in combination with TMZ in a lung cancer clinical trial.

Virotherapy: Finding New Utility In Nature's Most Dangerous Killers

Virotherapy: Finding New Utility in Nature’s Most Dangerous Killers Using Viruses to Combat Cancer Andrew Taber and Alex Cheung For centuries, viruses have been one of the greatest threats to human survival and propagation, and it has been one of medicine’s greatest challenges to create vaccines and methods to stall the onset of these viral diseases. That being said, it should come as a surprise that viruses are now being used as one of medicine’s most promising new methods to attack the next prominent threat to humanity: cancer. B S J H istory of V irotherapy Since the 1800’s, there have been case studies in which it was reported that cancer regression coincided significantly with viral infections. Dramatic reduction in the white blood cell count of patients (usually signifying an improving condition) was observed when the patients were infected by such viruses as influenza and chicken pox. Doctors and scientists at the time concluded that viruses, in certain environments, could temporarily improve a patient’s condition, especially in young children with compromised immune systems. After many years of animal and clinical research, it was found that viral infection is indeed a very potent method to treat cancer. But, at this point scientists had to use the very blunt instrument of naturally occurring viruses in their trials, which often led to subject death. (Kelly and Russel 2007) The solution was to design the viruses and delivery systems using genetic engineering so that the immune system would let the viruses through and so that the viruses would target the desired cell type. The tools needed to achieve this goal, however, were not developed until relatively recently. Until then, science used a method called targeted evolution to encourage the propagation of mutations that would result in viruses attacking cancer cells.When recombinant DNA technology was developed, the effectiveness of virotherapy could be even more directly controlled. Today, virotherapy is showing significant effectiveness in treating many cancers and diseases in mice, and trials have even shown improvements in treating advanced melanoma in humans (Nutting 2005). These results are too significant to be ignored, and scientists are wasting no time in developing new viruses to fight other diseases. One of the ways to solve the problems of cell targeting is to add cancer-specific binding proteins to the virus. Each type of cell has an outer membrane that acts as a selective barrier between the cell and its surroundings. All membranes are coated with proteins that are used to identify a cell and its purpose in the body. One way of thinking of these proteins is as nametags, and scientists’ job is to engineer these proteins so that viruses “know” where “Virotherapy can succeed where past methods have failed.” 16 • B erkeley S cientific J ournal • I nfectious D isease • F all 2010 • V olume 14 • I ssue 1