Review RNA Viruses As Virotherapy Agents Stephen J Russell Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905, USA
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Cancer Gene Therapy (2002) 9, 961 – 966 D 2002 Nature Publishing Group All rights reserved 0929-1903/02 $25.00 www.nature.com/cgt Review RNA viruses as virotherapy agents Stephen J Russell Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905, USA. RNA viruses are rapidly emerging as extraordinarily promising agents for oncolytic virotherapy. Integral to the lifecycles of all RNA viruses is the formation of double-stranded RNA, which activates a spectrum of cellular defense mechanisms including the activation of PKR and the release of interferon. Tumors are frequently defective in their PKR signaling and interferon response pathways, and therefore provide a relatively permissive substrate for the propagation of RNA viruses. For most of the oncolytic RNA viruses currently under study, tumor specificity is either a natural characteristic of the virus, or a serendipitous consequence of adapting the virus to propagate in human tumor cell lines. Further refinement and optimization of these oncolytic agents can be achieved through virus engineering. This article provides a summary of the current status of oncolytic virotherapy efforts for seven different RNA viruses, namely, mumps, Newcastle disease virus, measles virus, vesicular stomatitis virus, influenza, reovirus, and poliovirus. Cancer Gene Therapy (2002) 9, 961–966 doi:10.1038/sj.cgt.7700535 he majority of significant human and animal pathogenic double-stranded RNA is to stimulate release of interferons, Tviruses have RNA genomes. Influenza, measles, which activate PKR in adjacent uninfected cells, thereby mumps, rubella, polio, rabies, yellow fever, dengue, and protecting them from virus infection. Tumors are frequently Ebola hemorrhagic fever are among the better known human defective in their PKR signaling pathway, and therefore examples. However, for the field of oncolytic virotherapy, provide a relatively permissive substrate for the propagation RNA viruses present a vast and largely untapped resource. of RNA viruses. RNA virus specificity for tumor cells may RNA virus genomes range in size from 7 to 30 kb and may also be a consequence of specific receptor usage for virus be single-stranded (positive or negative polarity) or entry or for cell-to-cell fusion or, alternatively, may be due double-stranded, nonsegmented or segmented, with genome to the specific activity of a viral internal ribosome entry replication taking place in the cytoplasm or nucleus. At the site. time of writing this review, the most promising oncolytic For most of the oncolytic RNA viruses discussed in this RNA viruses are attenuated strains of mumps virus, review, tumor specificity is either a natural characteristic of Newcastle disease virus (NDV), measles virus, vesicular the virus, or a serendipitous consequence of adapting the stomatitis virus, human reovirus, poliovirus, and influenza virus to propagate in human tumor cell lines. However, virus. further refinement and optimization of oncolytic potency, The most important characteristic of an oncolytic virus is specificity, and therapeutic utility can be achieved through that it propagates more efficiently in tumors than in normal virus engineering. ‘‘Reverse genetics’’ systems for the rescue host tissues. For oncolytic DNA viruses, this tumor of positive-strand RNA viruses (e.g., poliovirus) from specificity is often determined at the transcriptional level complementary DNA are relatively simple because infec- and is ultimately dependent on the interactions between tious viruses can be generated from mRNA. In contrast, nuclear transcription factors and viral promoter/enhancer rescue systems from negative-strand RNA viruses (e.g., elements. Obviously, RNA viruses are not subject to the measles virus, influenza virus) are highly complex and have influence of nuclear transcription factors, and must rely on only recently become available because the minimal an alternative mechanistic basis for their preferential infectious unit for these viruses is the ribonucleoprotein replication in tumor cells. Integral to the life cycles of all polymerase complex. For segmented double-stranded RNA RNA viruses is the formation of double-stranded RNA, a viruses (e.g., reovirus), the problems are even more for- potent stimulator of PKR, a protein kinase that inhibits midable, and convenient strategies for virus engineering do protein synthesis and promotes apoptosis, thereby control- not yet exist. In general, there are three approaches to the ling the spread of the virus infection. Another action of engineering of RNA viruses that have been adopted in order to enhance their utility as oncolytic agents. First is to engineer the viral envelope or capsid proteins in an attempt to redirect virus entry through receptors expressed at high Received September 12, 2002. levels on the tumor cell surface. The second is to disable Address correspondence and reprint requests to: Dr Stephen J Russell, viral genes whose encoded proteins counter the cellular Molecular Medicine Program, Mayo Clinic, 200 First Street, SW Rochester, responses to double-stranded RNA and to interferon. The MN 55905, USA. E-mail: [email protected] third engineering strategy is to add into the viral genome RNA viruses as virotherapy agents SJ Russell 962 additional cistrons coding either for proteins that faci- fluid experienced complete disappearance with no recur- litate virus tracking or proteins that enhance the potential rence after intracavitary mumps virus administration. for killing of uninfected bystander tumor cells. In the In summary, attenuated mumps remains a highly promis- remainder of this article, we review the current status of ing oncolytic virus for the treatment of human malig- oncolytic virotherapy efforts for seven different RNA nancy, and further studies utilizing this agent are eagerly viruses, namely, mumps, NDV, measles virus, vesicular anticipated. stomatitis virus, influenza, reovirus, and poliovirus. How- ever, the reader is reminded that this list of seven is by no means exhaustive and that virtually any RNA virus may, with Newcastle disease virus appropriate engineering, have potential as an antitumor agent. NDV belongs to the Rubulavirus genus of the Paramyxovir- idae family.4 NDV is an economically important avian pathogen causing severe respiratory and central nervous Mumps virus system disease.6 However, tissue culture–adapted strains of the virus not only show greatly reduced virulence, but also Oncolytic virotherapy was very much in vogue in the 1950s, exhibit potent oncolytic activity. NDV strain 73-T has been 1960s, and early 1970s. At that time, numerous viruses were shown to replicate selectively in human tumor cells, inducing administered by several different routes to hundreds of rapid cell-to-cell fusion and tumor cell death.7 It has been patients with various treatment-refractory malignancies.1,2 suggested that NDV’s tumor cell activity is based on cancer- In general, the results were tantalizing, but ultimately specific defects in the interferon pathway,8 but formal proof disappointing. However, the most promising clinical study is lacking for this hypothesis. performed during that era was a study conducted in Japan The oncolytic potency of NDV strain 73-T has been very and reported in 1974 using a tissue culture adapted strain of convincingly demonstrated in several human tumor xeno- mumps virus.3 Mumps virus is a member of the genus graft models. Thus, a single local injection of NDV strain Paramyxovirus in the family Paramyxoviridae4 and was 73-T caused durable, complete regression of human neuro- selected for cancer virotherapy trials based on its propensity blastoma and fibrosarcoma xenografts grown in athymic to flourish in actively multiplying germ cells, causing mice.9,10 Also, in a more recent study,8 locally administered postpubertal mumps orchitis. As the virus is otherwise of virus was shown to inhibit the growth of epidermoid, colon, low pathogenicity (mumps is not fatal) and most adults have lung, breast, and prostate xenografts. Furthermore, intra- antibodies against mumps virus, it was considered reason- peritoneal virus was effective against subcutaneous IMR-32 able to test its therapeutic potential in human subjects with neuroblastoma xenografts. advanced cancer. A tissue culture suspension of the virus Based in part on the aforementioned mouse efficacy was, therefore, administered to 90 patients with various studies, a highly purified isolate of the naturally attenuated terminal malignancies, either by local application to the MK 107 vaccine strain of NDV was tested in a phase I tumor surface, intratumoral inoculation, oral, rectal, or clinical study in patients with advanced solid cancers.11 The intravenous route, or by inhalation. Toxicity was minimal strain of NDV used for this study was named PV 701 and is — limited to occasional febrile reactions, but the clinical distinct from the 73-T strain discussed above. The purpose responses were most encouraging. In 37 of 90 patients, the of the phase I study was to define the maximum tolerated tumor disappeared or decreased to less than half of its dose (MTD) and safety of single and multiple intravenous original size. Minor regressions were observed in an doses of PV 701 as a single agent in patients with cancer. additional of 42 patients. Tumor destruction was maximal Seventy-nine patients with advanced solid cancer, unre- several days after the virus was administered, but was often sponsive to standard therapy, were enrolled into the study, followed by long-term suppression