Background: With few exceptions, current chemotherapy and radiotherapy protocols only obtain a slightly prolonged\nsurvival with severe adverse effects in patients with advanced solid tumors. In particular, most solid malignancies not\namenable to radical surgery still carry a dismal prognosis, which unfortunately is also the case for relapsing disease after\nsurgery. Even though targeted therapies obtained good results, clinical experience showed that tumors eventually\ndevelop resistance. On the other hand, earlier attempts of cancer immunotherapy failed to show consistent efficacy.\nMore recently, a deeper knowledge of immunosuppression in the tumor microenvironment (TME) allowed the\ndevelopment of effective drugs: in particular, monoclonal antibodies targeting the so-called immune checkpoint\nmolecules yielded striking and lasting effects in some tumors. Unfortunately, these monoclonal antibodies are not\neffective in a majority of patients and are ineffective in several solid malignancies. Furthermore, due to their\nmechanism of action, checkpoint inhibitors often elicit autoimmune-like disease.\nMain body: The use of viruses as oncolytic agents (OVs) was considered in the past, while only recently OVs revealed a\nconnection with immunotherapy. However, their antitumoral potential has remained largely unexplored, due to safety\nconcerns and some limitations in the techniques to manipulate viruses. OV research was recently revived by a better\nknowledge of viral/cancer biology and advances in the methodologies to delete virulence/immune-escape related\ngenes from even complex viral genomes or â??to armâ? OVs with appropriate transgenes. Recently, the first oncolytic virus,\nthe HSV-1 based Talimogene Laherparepvec (T-VEC), was approved for the treatment of non-resectable melanoma in\nUSA and Europe.\nConclusion: OVs have the potential to become powerful agents of cancer immune and gene therapy. Indeed, in\naddition to their selective killing activity, they can act as versatile gene expression platforms for the delivery of\ntherapeutic genes. This is particularly true for viruses with a large DNA genome, that can be manipulated to address\nthe multiple immunosuppressive features of the TME. This review will focus on the open issues, on the most promising\nlines of research in the OV field and, more in general, on how OVs could be improved to achieve real clinical\nbreakthroughs in cancers that are usually difficult to treat by immunotherapy.
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