Development of targeted oncolytic virotherapeutics through translational research
ABSTRACT Oncolytic virotherapeutics is a promising platform for cancer treatment but the product class has yet been successful. The key to success is integration of bidirectional translational research to rapidly address issues encountered in the laboratory and the clinics.
We highlight the hurdles identified for the targeted oncolytic virotherapy approach, specifically those identified in clinical trials with wild-type viruses and first-generation targeted agents. We also analyze the translational research and development that has been applied to overcome these hurdles, including virus engineering and design improvements for next-generation virotherapeutics.
The iterative loop between the clinic and the lab can function as a major driving force to optimize products from this platform.
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ABSTRACT: Advanced-stage cancers are extremely difficult to treat and rarely result in a cure. The application of oncolytic viruses is a potential strategy for controlling advanced-stage cancer because intratumoral (i.t.) injection of an oncolytic virus, such as vaccinia virus, results in tumor cell lysis and subsequent release of tumor antigens into the microenvironment. Furthermore, the viruses can serve as a vehicle for delivering genes of interest to cancer cells. In the current study, we hypothesize that in tumor-bearing mice primed with DNA encoding an immunogenic foreign antigen, ovalbumin (OVA) followed by a boost with i.t. administration of vaccinia virus encoding the same foreign antigen, OVA, can generate enhanced antitumor effects through the combination of viral oncolysis and tumor-specific immunity. We observed that tumor-bearing mice primed with OVA DNA and boosted with vaccinia encoding OVA (Vac-OVA) generated significant therapeutic antitumor effects as well as induced significant levels of OVA-specific CD8+ T cells in two different tumor models. Furthermore, treatment with Vac-OVA not only kills the tumor and stromal cells directly but also renders the tumor cells and surrounding stromal cells susceptible to OVA-specific CD8+ T-cell killing, resulting in enhanced antitumor therapeutic effects. Thus, the current study may provide a novel therapeutic strategy for the control of advanced-stage cancers.Clinical Cancer Research 08/2009; 15(14):4581-8. DOI:10.1158/1078-0432.CCR-08-2685 · 8.19 Impact Factor
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ABSTRACT: Oncolytic viruses (OVs) are promising anticancer agents but like other cancer monotherapies, the genetic heterogeneity of human malignancies can lead to treatment resistance. We used a virus/cell-based assay to screen diverse chemical libraries to identify small molecules that could act in synergy with OVs to destroy tumor cells that resist viral infection. Several molecules were identified that aid in viral oncolysis, enhancing virus replication and spread as much as 1,000-fold in tumor cells. One of these molecules we named virus-sensitizers 1 (VSe1), was found to target tumor innate immune response and could enhance OV efficacy in animal tumor models and within primary human tumor explants while remaining benign to normal tissues. We believe this is the first example of a virus/cell-based "pharmacoviral" screen aimed to identify small molecules that modulate cellular response to virus infection and enhance oncolytic virotherapy.Molecular Therapy 04/2010; 18(6):1123-9. DOI:10.1038/mt.2010.67 · 6.43 Impact Factor
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ABSTRACT: Oncolytic viruses (OVs) have shown promise as cancer therapeutics in pre-clinical and clinical testing; however, it is unlikely that OVs will constitute a stand-alone treatment. Histone deacetylase inhibitors (HDIs) represent a class of anticancer agents known to influence epigenetic modifications of chromatin, alter gene expression and manipulate a variety of signaling pathways, in some cases blunting the cellular antiviral response. Recent studies have shown that combining OV therapy with HDI treatment enhances viral replication and synergistically induces the killing of cancer cells in vitro and in vivo, an effect that has now been demonstrated in variety of virus/HDI combinations. This review discusses the results obtained with the different OV/HDI combinations, the rationale supporting these combinations and the advantages for oncolytic virus therapy.Cytokine & growth factor reviews 04/2010; 21(2-3):153-9. DOI:10.1016/j.cytogfr.2010.03.002 · 6.54 Impact Factor