Paramyxoviruses Measles virus and Newcastle Disease Virus

Measles virus (MV) and Newcastle Disease virus (NDV) are members of the negative single-stranded RNA paramyxoviridae family (120). MV is a member of genus Morbillivirus whereas NDV is a member of the Rubulovirus genus that comprises mumps virus. These family members encode 6 to 7 covalently linked genes from a 15-to 16-kb genome and are enveloped viruses (83). In the case of MV, the hemagglutinin (H) attachment protein binds to one of two cellular receptors, CD46 or the signaling activation molecule. CD46 is frequently overexpressed on cancer cells (20). Given that other replicating RNA viruses were becoming noted for their oncolytic effects, it was decided to evaluate whether derivatives of the Edmonston-B-strain of measles virus (MV-Ed), which are live attenuated vaccines that have been effectively used for over 30 yr, exhibited similar properties. Indeed, intratumoral and intravenous inoculation of MV-Ed was found to induce the regression of human lymphoma in xenographed models (18,121). Further, using reverse genetic techniques, MV has now been genetically modified to express reporter genes and soluble marker peptides such as CEA, and have retained oncolytic activity against ovarian tumor cells (84,121-124). MV, which has the H envelope protein replaced by single chain anti-CD20 antibody was effectively able to target CD20 expressing cells (125). Similar strategies have been used to target plasma cells expressing CD38, indicating that these viruses can be modified to target different tumor types and avoid the limitation of only targeting CD46 expressing cells (many normal cells also express CD46) (126). The mechanisms underlying MVs tumor selectivity remains unknown, although it could involve defects in the innate immune signaling pathways described earlier (127,128).

NDV and even mumps virus was first noted to replicate in selected tumors in the 1950s. NDV, which binds to sialic acid containing glycoconjugates whose exact identification remain to be elucidated, has been found to exhibit oncolytic effects against human neuroblastoma, fibrosarcoma, colon, breast, and prostate xenografts in nude mice (129). Based on these studies, a replication-competent strain of NDV, referred to as PV701 has been examined in phase I studies on a variety of advanced solid tumors, that were unresponsive to standard therapy (100). Approximately 10% tumor responses were reported using PV701 and phase II trials are now in progress (130-132). In addition to this study, another live attenuated NDV strain, referred to as MTH-68/H was used in patients with glioblastoma multiforme (133). Although a small study, four cases of advanced high grade glioma that had failed standard therapies responded well to the treatment with survival rates of 5 to 9 yr (as opposed to 6 mo using standard treatments) being stated. NDV has been reported to be genetically manipulative, but few studies are presently available on these types of study.

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