title: Meningeal myeloma deposits adversely impact the therapeutic index of an oncolytic VSV.
abstract: Vesicular stomatitis virus (VSV) is neuropathogenic in rodents but can be attenuated 50-fold by engineering the mouse interferon-beta (IFN-β) gene into its genome. Intravenously administered VSVs encoding IFN-β have potent activity against subcutaneous tumors in the 5TGM1 mouse myeloma model, without attendant neurotoxicity. However, when 5TGM1 tumor cells were seeded intravenously, virus-treated mice with advanced myeloma developed clinical signs suggestive of meningoencephalitis. Co-administration of a known active antimyeloma agent did not prolong survival, further suggesting that deaths were due to viral toxicity, not tumor burden. Histological analysis revealed that systemically administered 5TGM1 cells seed to the CNS, forming meningeal tumor deposits, and that VSV infects and destroys these tumors. Death is presumably a consequence of meningeal damage and/or direct transmission of virus to adjacent neural tissue. In light of these studies, extreme caution is warranted in clinical testing of attenuated VSVs, particularly in patients with CNS tumor deposits.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Yarde
authors.forename: S
authors.initials: S
authors.lastname: Naik
authors.forename: R A
authors.initials: RA
authors.lastname: Nace
authors.forename: K-W
authors.initials: KW
authors.lastname: Peng
authors.forename: M J
authors.initials: MJ
authors.lastname: Federspiel
authors.forename: S J
authors.initials: SJ
authors.lastname: Russell
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016899:Interferon-beta / Q000235:genetics; D008577:Meningeal Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics*; D018116:Vesiculovirus / Q000235:genetics*
chemical_list: D016899:Interferon-beta