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

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 - Mol. Ther. (2010)

Bottom Line: We have found that JX-594 killed all MG cell lines tested in vitro.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta, Canada. xlun@ucalgary.ca

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).

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i.t. administration of JX-594/JX-594m inhibited tumor growth and prolonged survival of immunocompetent animals-bearing intracranial glioma. (a) Kaplan–Meier survival of rats harboring intracranial RG2 tumor treated with PBS (n = 8) or i.t. administration of JX-594 (n = 7, 5 × 107 PFUs /rat) or i.t. administration of JX-594m (n = 8, 5 × 107/rat, at days 1 and 4). Arrows indicates virus administration. (b) Representative BLI obtained at days 4, 11, and 14 after tumor implantation of RG2-Fluc and treatment with JX-594, JX-594m, or PBS. (c) Quantification of the BLI. (d) Kaplan–Meier survival curves of C57/BL6 mice harboring GL261 tumor treated with control (PBS, n = 7), JX-594 (n = 7, 1 × 107 PFU/rat for three times, at days 1, 4, and 10) or JX-594m (n = 8). Arrows indicate the day of virus administration. BLI, bioluminescence image; i.t., intracranial; PBS, phosphate-buffered saline; PFU, plaque-forming unit; p.i., postinfection.
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fig2: i.t. administration of JX-594/JX-594m inhibited tumor growth and prolonged survival of immunocompetent animals-bearing intracranial glioma. (a) Kaplan–Meier survival of rats harboring intracranial RG2 tumor treated with PBS (n = 8) or i.t. administration of JX-594 (n = 7, 5 × 107 PFUs /rat) or i.t. administration of JX-594m (n = 8, 5 × 107/rat, at days 1 and 4). Arrows indicates virus administration. (b) Representative BLI obtained at days 4, 11, and 14 after tumor implantation of RG2-Fluc and treatment with JX-594, JX-594m, or PBS. (c) Quantification of the BLI. (d) Kaplan–Meier survival curves of C57/BL6 mice harboring GL261 tumor treated with control (PBS, n = 7), JX-594 (n = 7, 1 × 107 PFU/rat for three times, at days 1, 4, and 10) or JX-594m (n = 8). Arrows indicate the day of virus administration. BLI, bioluminescence image; i.t., intracranial; PBS, phosphate-buffered saline; PFU, plaque-forming unit; p.i., postinfection.

Mentions: RG2-bearing rats were treated i.t. with multiple doses of JX-594 or JX-594m (at days 1 and 4). Treatment with virus prolonged survival (median survival 16 days for phosphate-buffered saline (PBS) control, 26 days for JX-594 and 27 days for JX-594m); some rats treated with JX-594 (one rat survived for 35 days) or JX-594m (two rats survived for 36 and 41 days, respectively) were “long-term” survivors (Figure 2a, long-rank test, P < 0.0001 PBS and JX-594 or JX-594m). Survival with JX-594 or JX-594m were not significantly different (log-rank test, P = 0.3288).


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

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 - Mol. Ther. (2010)

i.t. administration of JX-594/JX-594m inhibited tumor growth and prolonged survival of immunocompetent animals-bearing intracranial glioma. (a) Kaplan–Meier survival of rats harboring intracranial RG2 tumor treated with PBS (n = 8) or i.t. administration of JX-594 (n = 7, 5 × 107 PFUs /rat) or i.t. administration of JX-594m (n = 8, 5 × 107/rat, at days 1 and 4). Arrows indicates virus administration. (b) Representative BLI obtained at days 4, 11, and 14 after tumor implantation of RG2-Fluc and treatment with JX-594, JX-594m, or PBS. (c) Quantification of the BLI. (d) Kaplan–Meier survival curves of C57/BL6 mice harboring GL261 tumor treated with control (PBS, n = 7), JX-594 (n = 7, 1 × 107 PFU/rat for three times, at days 1, 4, and 10) or JX-594m (n = 8). Arrows indicate the day of virus administration. BLI, bioluminescence image; i.t., intracranial; PBS, phosphate-buffered saline; PFU, plaque-forming unit; p.i., postinfection.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2990519&req=5

fig2: i.t. administration of JX-594/JX-594m inhibited tumor growth and prolonged survival of immunocompetent animals-bearing intracranial glioma. (a) Kaplan–Meier survival of rats harboring intracranial RG2 tumor treated with PBS (n = 8) or i.t. administration of JX-594 (n = 7, 5 × 107 PFUs /rat) or i.t. administration of JX-594m (n = 8, 5 × 107/rat, at days 1 and 4). Arrows indicates virus administration. (b) Representative BLI obtained at days 4, 11, and 14 after tumor implantation of RG2-Fluc and treatment with JX-594, JX-594m, or PBS. (c) Quantification of the BLI. (d) Kaplan–Meier survival curves of C57/BL6 mice harboring GL261 tumor treated with control (PBS, n = 7), JX-594 (n = 7, 1 × 107 PFU/rat for three times, at days 1, 4, and 10) or JX-594m (n = 8). Arrows indicate the day of virus administration. BLI, bioluminescence image; i.t., intracranial; PBS, phosphate-buffered saline; PFU, plaque-forming unit; p.i., postinfection.
Mentions: RG2-bearing rats were treated i.t. with multiple doses of JX-594 or JX-594m (at days 1 and 4). Treatment with virus prolonged survival (median survival 16 days for phosphate-buffered saline (PBS) control, 26 days for JX-594 and 27 days for JX-594m); some rats treated with JX-594 (one rat survived for 35 days) or JX-594m (two rats survived for 36 and 41 days, respectively) were “long-term” survivors (Figure 2a, long-rank test, P < 0.0001 PBS and JX-594 or JX-594m). Survival with JX-594 or JX-594m were not significantly different (log-rank test, P = 0.3288).

Bottom Line: We have found that JX-594 killed all MG cell lines tested in vitro.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta, Canada. xlun@ucalgary.ca

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).

Show MeSH
Related in: MedlinePlus