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PMID: 20808290 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma.

Molecular therapy : the journal of the American Society of Gene Therapy ·Vol. 18 ·No. 11 ·2010-11-00 ·Pages 1927-36

Lun X, Chan J, Zhou H, Sun B, Kelly JJ, Stechishin OO, Bell JC, Parato K, Hu K, Vaillant D, Wang J, Liu TC, Breitbach C, Kirn D, Senger DL, Forsyth PA

Abstract

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).

MeSH Terms
Animals Antibiotics, Antineoplastic/therapeutic use Brain Neoplasms/genetics,therapy Combined Modality Therapy Disease Models, Animal Female Genetic Vectors/therapeutic use Glioma/genetics,therapy Granulocyte-Macrophage Colony-Stimulating Factor/analysis,genetics Immunoenzyme Techniques Male Mice Mice, Inbred C57BL Mice, Knockout Oncolytic Virotherapy Rats Rats, Inbred F344 Sirolimus/therapeutic use Survival Rate Transgenes/physiology Tumor Cells, Cultured Vaccines, Synthetic/therapeutic use Vaccinia virus/genetics Virus Replication
Chemicals
Antibiotics, Antineoplastic Vaccines, Synthetic Granulocyte-Macrophage Colony-Stimulating Factor Sirolimus
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Lun XueQing
Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta, Canada. xlun@ucalgary.ca
Chan Jennifer
Zhou Hongyuan
Sun Beichen
Kelly John J P
Stechishin Owen Owen
Bell John C
Parato Kelley
Hu Kang
Vaillant Dominique
Wang Jiahu
Liu Ta-Chiang
Breitbach Caroline
Kirn David
Senger Donna L
Forsyth Peter A
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Article Info
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
Abbr.
Mol Ther
ISSN
1525-0024
DOI
10.1038/mt.2010.183
Email
xlun@ucalgary.ca
Published
2010-11-00
Epub
2010-00-31
Pages
1927-36
Language
English
Region
United States
NLM ID
100890581
PMCID
PMC2990519
Subset
IM
External Links
PubMed source DOI: 10.1038/mt.2010.183 PMC Full Text View journal details
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