Efficacy and safety evaluation of human reovirus type 3 in immunocompetent animals: racine and nonhuman primates.
OBJECTIVE
Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates.


METHODS
Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys.


RESULTS
Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus' antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates.


CONCLUSIONS
These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.
Yang
Wen Qing
WQ
Departments of Oncology and Clinical Neurosciences, University of Calgary, and Tom Baker Cancer Centre, Calgary, Alberta, Canada.
Lun
Xueqing
X
Palmer
Cheryl Ann
CA
Wilcox
M Elizabeth
ME
Muzik
Huong
H
Shi
Zhong Qiao
ZQ
Dyck
Richard
R
Coffey
Matt
M
Thompson
Brad
B
Hamilton
Mark
M
Nishikawa
Sandra G
SG
Brasher
Penny M A
PM
Fonseca
Kevin
K
George
David
D
Rewcastle
N Berry
NB
Johnston
Randal N
RN
Stewart
Doug
D
Lee
Patrick W K
PW
Senger
Donna L
DL
Forsyth
Peter A
PA
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D004660:Encephalitis / Q000209:etiology / Q000473:pathology; D005260:Female; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy* / Q000821:virology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G; D017403:In Situ Hybridization; D008252:Macaca fascicularis; D008297:Male; D012089:Mammalian orthoreovirus 3 / Q000302:isolation & purification / Q000502:physiology*; D018782:Maze Learning; D023421:Models, Animal; D009500:Neutralization Tests; D051381:Rats; D011916:Rats, Inbred F344; D011923:Rats, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D007074:Immunoglobulin G; D049452:Green Fluorescent Proteins