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Oncolytic bluetongue viruses: promise, progress, and perspectives.

ABSTRACT: Humans are sero-negative toward bluetongue viruses (BTVs) since BTVs do not infect normal human cells. Infection and selective degradation of several human cancer cell lines but not normal ones by five US BTV serotypes have been investigated. We determined the susceptibilities of many normal and human cancer cells to BTV infections and made comparative kinetic analyses of their cytopathic effects, survival rates, ultra-structural changes, cellular apoptosis and necrosis, cell cycle arrest, cytokine profiles, viral genome, mRNAs, and progeny titers. The wild-type US BTVs, without any genetic modifications, could preferentially infect and degrade several types of human cancer cells but not normal cells. Their selective and preferential BTV-degradation of human cancer cells is viral dose-dependent, leading to effective viral replication, and induced apoptosis. Xenograft tumors in mice were substantially reduced by a single intratumoral BTV injection in initial in vivo experiments. Thus, wild-type BTVs, without genetic modifications, have oncolytic potentials. They represent an attractive, next generation of oncolytic viral approach for potential human cancer therapy combined with current anti-cancer agents and irradiation.

SUBMITTER: Li JK

PROVIDER: S-EPMC3128942 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Oncolytic bluetongue viruses: promise, progress, and perspectives.

Li Joseph K-K JK

Frontiers in microbiology 20110316

Humans are sero-negative toward bluetongue viruses (BTVs) since BTVs do not infect normal human cells. Infection and selective degradation of several human cancer cell lines but not normal ones by five US BTV serotypes have been investigated. We determined the susceptibilities of many normal and human cancer cells to BTV infections and made comparative kinetic analyses of their cytopathic effects, survival rates, ultra-structural changes, cellular apoptosis and necrosis, cell cycle arrest, cytok ...[more]

PMID: 21747785

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

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Oncolytic bluetongue viruses: promise, progress, and perspectives.

Publications

Oncolytic bluetongue viruses: promise, progress, and perspectives.

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