Identification of Genetically Modified Maraba Virus as an Oncolytic Rhabdovirus

To expand our current array of safe and potent oncolytic viruses, we screened a variety of wild-type (WT) rhabdoviruses against a panel of tumor cell lines. Our screen identified a number of viruses with varying degrees of killing activity. Maraba virus was the most potent of these strains. We built...

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Published inMolecular therapy Vol. 18; no. 8; pp. 1440 - 1449
Main Authors Brun, Jan, McManus, Dan, Lefebvre, Charles, Hu, Kang, Falls, Theresa, Atkins, Harold, Bell, John C, McCart, J. Andrea, Mahoney, Douglas, Stojdl, David F
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.08.2010
Elsevier Limited
Nature Publishing Group
Subjects
Animals
Cancer
Cell Line
Cell Line, Tumor
Cell Survival
Cells
Cercopithecus aethiops
Humans
Immunology
Infections
Mice
Mice, Inbred BALB C
Mutation
Neoplasms - therapy
Oncolytic Virotherapy - methods
Original
Phylogeny
Rabies
Research centers
Reverse Transcriptase Polymerase Chain Reaction
Rhabdoviridae - genetics
Vero Cells
Viruses
Xenograft Model Antitumor Assays
Toronto Ontario Canada
Canada
Ottawa Ontario Canada
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Summary:To expand our current array of safe and potent oncolytic viruses, we screened a variety of wild-type (WT) rhabdoviruses against a panel of tumor cell lines. Our screen identified a number of viruses with varying degrees of killing activity. Maraba virus was the most potent of these strains. We built a recombinant system for the Maraba virus platform, engineered a series of attenuating mutations to expand its therapeutic index, and tested their potency in vitro and in vivo. A double mutant (MG1) strain containing both G protein (Q242R) and M protein (L123W) mutations attenuated Maraba virus in normal diploid cell lines, yet appeared to be hypervirulent in cancer cells. This selective attenuation was mediated through interferon (IFN)-dependent and -independent mechanisms. Finally, the Maraba MG1 strain had a 100-fold greater maximum tolerable dose (MTD) than WT Maraba in vivo and resulted in durable cures when systemically administered in syngeneic and xenograft models. In summary, we report a potent new oncolytic rhabdovirus platform with unique tumor-selective attenuating mutations.
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The first two authors contributed equally to this work.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2010.103