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 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.
Brun
Jan
J
Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
McManus
Dan
D
Lefebvre
Charles
C
Hu
Kang
K
Falls
Theresa
T
Atkins
Harold
H
Bell
John C
JC
McCart
J Andrea
JA
Mahoney
Douglas
D
Stojdl
David F
DF
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D010802:Phylogeny; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012209:Rhabdoviridae / Q000235:genetics*; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays