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

Xueqing Lun, Jennifer Chan, Hongyuan Zhou, Beichen Sun, John J.P. Kelly, Owen Owen Stechishin, John C. Bell, Kelley Parato, Kang Hu, Dominique Vaillant, Jiahu Wang, Ta Chiang Liu, Caroline Breitbach, David Kirn, Donna L. Senger, Peter A. Forsyth

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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).

Original languageEnglish
Pages (from-to)1927-1936
Number of pages10
JournalMolecular Therapy
Volume18
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

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    Lun, X., Chan, J., Zhou, H., Sun, B., Kelly, J. J. P., Stechishin, O. O., Bell, J. C., Parato, K., Hu, K., Vaillant, D., Wang, J., Liu, T. C., Breitbach, C., Kirn, D., Senger, D. L., & Forsyth, P. A. (2010). Efficacy and safety/toxicity study of recombinant vaccinia virus JX-594 in two immunocompetent animal models of glioma. Molecular Therapy, 18(11), 1927-1936. https://doi.org/10.1038/mt.2010.183