Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma.
The purpose of this study was to investigate the oncolytic potential of the recombinant, granulocyte macrophage colony-stimulating factor (GM-CSF)-expressing vaccinia virus (VV) JX-594 in experimental malignant glioma (MGs) in vitro and in immunocompetent rodent models. We have found that JX-594 killed all MG cell lines tested in vitro. Intratumoral (i.t.) administration of JX-594 significantly inhibited tumor growth and prolonged survival in rats-bearing RG2 intracranial (i.c.) tumors and mice-bearing GL261 brain tumors. Combination therapy with JX-594 and rapamycin significantly increased viral replication and further prolonged survival in both immunocompetent i.c. MG models with several animals considered "cured" (three out of seven rats >120 days, terminated experiment). JX-594 infected and killed brain tumor-initiating cells (BTICs) from patient samples grown ex vivo, and did so more efficiently than other oncolytic viruses MYXV, Reovirus type-3, and VSV(ΔM51). Additional safety/toxicity studies in nontumor-bearing rodents treated with a supratherapeutic dose of JX-594 demonstrated GM-CSF-dependent inflammation and necrosis. These results suggest that i.c. administered JX-594 triggers a predictable GM-CSF-mediated inflammation in murine models. Before proceeding to clinical trials, JX-594 should be evaluated in the brains of nonhuman primates and optimized for the viral doses, delivery routes as well as the combination agents (e.g., mTOR inhibitors).
Lun
XueQing
X
Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta, Canada. xlun@ucalgary.ca
Chan
Jennifer
J
Zhou
Hongyuan
H
Sun
Beichen
B
Kelly
John J P
JJ
Stechishin
Owen Owen
OO
Bell
John C
JC
Parato
Kelley
K
Hu
Kang
K
Vaillant
Dominique
D
Wang
Jiahu
J
Liu
Ta-Chiang
TC
Breitbach
Caroline
C
Kirn
David
D
Senger
Donna L
DL
Forsyth
Peter A
PA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors / Q000627:therapeutic use; D005910:Glioma / Q000235:genetics / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000032:analysis / Q000235:genetics*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050130:Oncolytic Virotherapy; D051381:Rats; D011916:Rats, Inbred F344; D020123:Sirolimus / Q000627:therapeutic use*; D015996:Survival Rate; D019076:Transgenes / Q000502:physiology; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000627:therapeutic use; D014616:Vaccinia virus / Q000235:genetics*; D014779:Virus Replication
D000903:Antibiotics, Antineoplastic; D014614:Vaccines, Synthetic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020123:Sirolimus
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