1. Efficacy and Safety/Toxicity Study of Recombinant Vaccinia Virus JX-594 in Two Immunocompetent Animal Models of Glioma.
- Author
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XueQing Lun, Chan, Jennifer, Hongyuan Zhou, Beichen Sun, Kelly, John J. P., Stechishin, Owen Owen, Bell, John C., Parato, Kelley, Kang Hu, Vaillant, Dominique, Jiahu Wang, Ta-Chiang Liu, Breitbach, Caroline, Kirn, David, Senger, Donna L., and Forsyth, Peter A.
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VACCINIA , *GRANULOCYTE-macrophage colony-stimulating factor , *GLIOMAS , *IMMUNOCOMPETENT cells , *TOXICITY testing , *ANIMAL models in research , *CELL lines , *CLINICAL trials - 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 VSVΔM51. 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). [ABSTRACT FROM AUTHOR]
- Published
- 2010
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