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 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). 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). IntroductionMalignant glioma (MGs) are the most common primary intracranial (i.c.) malignancy, with survival times remaining relatively static over the past few decades. Oncolytic viruses (OVs) show promising treatment efficacy in models of MGs, with several OVs being tested in preclinical models of MGs1Martuza RL Malick A Markert JM Ruffner KL Coen DM Experimental therapy of human glioma by means of a genetically engineered virus mutant.Science. 1991; 252: 854-856Crossref PubMed Scopus (768) Google Scholar,2Fueyo J Gomez-Manzano C Alemany R Lee PS McDonnell TJ Mitlianga P et al.A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo.Oncogene. 2000; 19: 2-12Crossref PubMed Scopus (623) Google Scholar,3Wilcox ME Yang W Senger D Rewcastle NB Morris DG Brasher PM et al.Reovirus as an oncolytic agent against experimental human malignant gliomas.J Natl Cancer Inst. 2001; 93: 903-912Crossref PubMed Scopus (192) Google Scholar,4Gromeier M Lachmann S Rosenfeld MR Gutin PH Wimmer E Intergeneric poliovirus recombinants for the treatment of malignant glioma.Proc Natl Acad Sci USA. 2000; 97: 6803-6808Crossref PubMed Scopus (296) Google Scholar,5Lun X Yang W Alain T Shi ZQ Muzik H Barrett JW et al.Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas.Cancer Res. 2005; 65: 9982-9990Crossref PubMed Scopus (131) Google Scholar,6Lun X Senger DL Alain T Oprea A Parato K Stojdl D et al.Effects of intravenously administered recombinant vesicular stomatitis virus (VSV(ΔM51)) on multifocal and invasive gliomas.J Natl Cancer Inst. 2006; 98: 1546-1557Crossref PubMed Scopus (80) Google Scholar and some evaluated in early clinical trials.7Markert JM Medlock MD Rabkin SD Gillespie GY Todo T Hunter WD et al.Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial.Gene Ther. 2000; 7: 867-874Crossref PubMed Scopus (810) Google Scholar,8Chiocca EA Abbed KM Tatter S Louis DN Hochberg FH Barker F et al.A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting.Mol Ther. 2004; 10: 958-966Abstract PubMed Scopus Google JM E E et trial of oncolytic virus in recurrent Ther. 2006; PubMed Scopus Google P D C Morris D et al.A phase I trial of administration of in with recurrent malignant Ther. PubMed Scopus Google S J R R M et injection into the brain to of glioma: and Ther. 2004; PubMed Scopus Google R M R D J et potential for efficacy of the herpes simplex virus injection into human malignant glioma: a of Ther. PubMed Scopus Google EA trial of oncolytic herpes virus G207 of and viral Ther. PubMed Scopus Google JM W S E M et trial of mutant herpes simplex virus G207 for recurrent Ther. PubMed Scopus Google Scholar These found that therapy is with a few more OVs be found for the treatment of virus (VV) is a virus with a for several over other as is to replication and are is into and is in models and JW J et al.A recombinant vaccinia virus human and in a J PubMed Scopus Google A JM JM a and and PubMed Scopus Google Scholar is clinical with as a for are PM therapy targeting and in Ther. 7: PubMed Scopus Google T et of a oncolytic in with primary a phase I PubMed Scopus Google of replicating have efficacy in preclinical MG J D et effect of vaccinia virus in glioma Res. Google H R et of administered oncolytic vaccinia for malignant is by combination therapy with rapamycin Cancer Res. PubMed Scopus Google Scholar and other M Lee J et the replicating oncolytic effect and the effect of tumor Ther. 2000; 7: PubMed Scopus Google Lee et oncolytic and therapy for with a Ther. 2006; PubMed Scopus Google E RL et of human tumors in with an intravenously oncolytic vaccinia Res. PubMed Scopus Google I et virus and human and murine tumors in Ther. PubMed Scopus Google H E R et for a vaccinia PubMed Scopus Google Scholar potential of a replicating a mutant and vaccinia growth factor of the was to several tumor in murine models significant JM Lee J et therapy with a vaccinia virus mutant and vaccinia growth factor Res. 2001; Google Scholar is administered intravenously in nonhuman S H et and delivery of and a replicating mutant vaccinia virus in nonhuman Ther. 2006; PubMed Scopus Google Scholar and in rodent MG H R et of administered oncolytic vaccinia for malignant is by combination therapy with rapamycin Cancer Res. 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JX-594 in found significant antitumor with viral replication and of the T et of a oncolytic in with primary a phase I PubMed Scopus Google of this study to investigate the efficacy and safety/toxicity of JX-594 and administered in immunocompetent rodent and human brain tumor-initiating cells and and all tested glioma cell lines in MG cell lines and all to and killed as demonstrated by effect and with was to other OVs and Reovirus found efficacy and a of cell lines to and to viral viral cell lines to with than the found all the cells of and did cells on the of JX-594 and administered in immunocompetent and murine models of rats treated with of JX-594 and with virus prolonged survival survival for for JX-594 and for some rats treated with JX-594 for rats for and days, P and JX-594 with JX-594 significantly P administration of inhibited tumor growth and prolonged survival of immunocompetent intracranial survival of rats intracranial RG2 tumor treated with administration of JX-594 administration of and virus and tumor of and treatment with of the survival of GL261 tumor treated with JX-594 for and the of virus a for tumor in of tumors. of animals increased by tumor and on and treated rats a that increased and and did a by and of the survival in a MG to other OVs to MYXV, and in treated on and GL261 tumor and found survival was significantly P and JX-594 out of treated with considered both JX-594 and survival the that the of the in this be for survival in this therapy with rapamycin in vitro and virus replication in combination therapy with rapamycin JX-594 in cell with with Combination treatment in cell than treatment in both RG2 and GL261 glioma lines therapy with rapamycin in vitro and viral replication in of rodents glioma cell lines the and with JX-594 rapamycin both as by viral replication and of in rapamycin treated RG2 rats viral replication of in rapamycin treated GL261 rapamycin viral replication in in the RG2 the days, virus virus was JX-594 days, for 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and X Alain T H MG et al.Myxoma virus for glioma in immunocompetent administration routes and with Res. 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PubMed Scopus Google promising activity of JX-594 in rodent models for clinical of JX-594 in with injection of a supratherapeutic dose of JX-594 into the rodent brain was with be to injection of JX-594 into brain and should be in this patient JX-594 of tumors in and in with be in with tumors. as MG are treated with inflammation and be of promising in nontumor-bearing rodents to be considered JX-594 and inflammation and necrosis. are more with than and more and than other ME Yang W Senger D Rewcastle NB Morris DG Brasher PM et al.Reovirus as an oncolytic agent against experimental human malignant gliomas.J Natl Cancer Inst. 2001; 93: 903-912Crossref PubMed Scopus (192) Google Scholar,5Lun X Yang W Alain T Shi ZQ Muzik H Barrett JW et al.Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas.Cancer Res. 2005; 65: 9982-9990Crossref PubMed Scopus (131) Google H R et of administered oncolytic vaccinia for malignant is by combination therapy with rapamycin Cancer Res. PubMed Scopus Google X ME Muzik H Shi ZQ et and of human in immunocompetent and nonhuman Cancer Res. 2004; 10: PubMed Scopus Google X Alain T H MG et al.Myxoma virus for glioma in immunocompetent administration routes and with Res. PubMed Scopus Google Gillespie et and of the oncolytic herpes simplex virus and with Ther. PubMed Scopus Google D K JM et administration of adenovirus in combination with produces a Ther. PubMed Scopus Google J H M Wimmer E and in of recombinant oncolytic PubMed Scopus Google T F Rabkin SD F et and of a replicating herpes simplex virus in Ther. 2000; PubMed Scopus (80) Google R M TJ JW C et study of administration of a virus in in of a phase clinical trial for with recurrent Ther. 19: PubMed Scopus Google Scholar for i.c. a X Senger DL Alain T Oprea A Parato K Stojdl D et al.Effects of intravenously administered recombinant vesicular stomatitis virus (VSV(ΔM51)) on multifocal and invasive gliomas.J Natl Cancer Inst. 2006; 98: 1546-1557Crossref PubMed Scopus (80) Google be to MG MG with H A E M S S et survival in a patient with PubMed Scopus Google Scholar i.c. have and are M Yang W C J et with and of in human Cancer Res. PubMed Scopus Google S intracranial in with PubMed Google Scholar OVs tested in clinical clinical results are JM Medlock MD Rabkin SD Gillespie GY Todo T Hunter WD et al.Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial.Gene Ther. 2000; 7: 867-874Crossref PubMed Scopus (810) Google Scholar,8Chiocca EA Abbed KM Tatter S Louis DN Hochberg FH Barker F et al.A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting.Mol Ther. 2004; 10: 958-966Abstract PubMed Scopus Google JM E E et trial of oncolytic virus in recurrent Ther. 2006; PubMed Scopus Google P D C Morris D et al.A phase I trial of administration of in with recurrent malignant Ther. PubMed Scopus Google S J R R M et injection into the brain to of glioma: and Ther. 2004; PubMed Scopus Google R M R D J et potential for efficacy of the herpes simplex virus injection into human malignant glioma: a of Ther. PubMed Scopus Google EA trial of oncolytic herpes virus G207 of and viral Ther. PubMed Scopus Google JM W S E M et trial of mutant herpes simplex virus G207 for recurrent Ther. PubMed Scopus Google Scholar are and in trial have an of tumor S J R R M et injection into the brain to of glioma: and Ther. 2004; PubMed Scopus Google R M R D J et potential for efficacy of the herpes simplex virus injection into human malignant glioma: a of Ther. PubMed Scopus Google EA trial of oncolytic herpes virus G207 of and viral Ther. 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PubMed Scopus Google X ME Muzik H Shi ZQ et and of human in immunocompetent and nonhuman Cancer Res. 2004; 10: PubMed Scopus Google Scholar and and replication The recombinant JX-594 and are from the JX-594 was by of human and into the viral murine viruses and on Lee et oncolytic and therapy for with a Ther. 2006; PubMed Scopus Google in vitro viral replication cells infected with JX-594 an of and cells with of of Lee et oncolytic and therapy for with a Ther. 2006; PubMed Scopus Google and effect infected with and was by X Yang W Alain T Shi ZQ Muzik H Barrett JW et al.Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas.Cancer Res. 2005; 65: 9982-9990Crossref PubMed Scopus (131) Google H R et of administered oncolytic vaccinia for malignant is by combination therapy with rapamycin Cancer Res. PubMed Scopus Google X ME Muzik H Shi ZQ et and of human in immunocompetent and nonhuman Cancer Res. 2004; 10: PubMed Scopus Google Scholar We the results with of and Reovirus combination therapy with rapamycin was viral vitro effect with a and a and and with primary the murine and was as the with to and was by the of with studies of glioma models in immunocompetent investigate rats with RG2 cells as X Yang W Alain T Shi ZQ Muzik H Barrett JW et al.Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas.Cancer Res. 2005; 65: 9982-9990Crossref PubMed Scopus (131) Google X ME Muzik H Shi ZQ et and of human in immunocompetent and nonhuman Cancer Res. 2004; 10: PubMed Scopus Google Scholar treated with and tumor animals treated with animals for The times of to efficacy the tumors to be both and tumor rats tumor treated with JX-594 as a and tumor with the to from tumors. on in the region of S M S et of intracranial with tumor and in tumor growth and treatment 2006; PubMed Scopus Google therapy with RG2 GL261 cells treated rapamycin infected with JX-594 and viral replication in vivo, animals treated with tumor a dose of was for with other virus animals the in of combination therapy i.c. animals into the tumor rapamycin rapamycin other for JX-594 administered and and JX-594 the on an tumor animals into tumor rapamycin rapamycin for administered and and of i.c. administration of in nontumor-bearing rats rats i.c. with JX-594 and of and X Yang W Alain T Shi ZQ Muzik H Barrett JW et al.Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas.Cancer Res. 2005; 65: 9982-9990Crossref PubMed Scopus (131) Google X ME Muzik H Shi ZQ et and of human in immunocompetent and nonhuman Cancer Res. 2004; 10: PubMed Scopus Google Scholar for other the and viral animals and viral i.c. administration the effect of against ex by and of We as A X Senger DL et of human cells of PubMed Scopus Google X S et a for the treatment of invasive glioma by the PubMed Scopus Google Scholar and and in in infected with was The was as the viral cells in and into the of was viral viral and viral in infected with The to of to and and for by the The with the of P and considered to be significant P with JX-594 and and glioma cell lines that are to other oncolytic viruses in vitro. with and results JX-594 and glioma cell with Combination therapy with rapamycin replication and rapamycin treatment further prolonged survival in RG2 with JX-594 and safety/toxicity studies in immunocompetent with in the brain intracranial IntroductionMalignant glioma (MGs) are the most common primary intracranial (i.c.) malignancy, with survival times remaining relatively static over the past few decades. Oncolytic viruses (OVs) show promising treatment efficacy in models of MGs, with several OVs being tested in preclinical models of MGs1Martuza RL Malick A Markert JM Ruffner KL Coen DM Experimental therapy of human glioma by means of a genetically engineered virus mutant.Science. 1991; 252: 854-856Crossref PubMed Scopus (768) Google Scholar,2Fueyo J Gomez-Manzano C Alemany R Lee PS McDonnell TJ Mitlianga P et al.A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo.Oncogene. 2000; 19: 2-12Crossref PubMed Scopus (623) Google Scholar,3Wilcox ME Yang W Senger D Rewcastle NB Morris DG Brasher PM et al.Reovirus as an oncolytic agent against experimental human malignant gliomas.J Natl Cancer Inst. 2001; 93: 903-912Crossref PubMed Scopus (192) Google Scholar,4Gromeier M Lachmann S Rosenfeld MR Gutin PH Wimmer E Intergeneric poliovirus recombinants for the treatment of malignant glioma.Proc Natl Acad Sci USA. 2000; 97: 6803-6808Crossref PubMed Scopus (296) Google Scholar,5Lun X Yang W Alain T Shi ZQ Muzik H Barrett JW et al.Myxoma virus is a novel oncolytic virus with significant antitumor activity against experimental human gliomas.Cancer Res. 2005; 65: 9982-9990Crossref PubMed Scopus (131) Google Scholar,6Lun X Senger DL Alain T Oprea A Parato K Stojdl D et al.Effects of intravenously administered recombinant vesicular stomatitis virus (VSV(ΔM51)) on multifocal and invasive gliomas.J Natl Cancer Inst. 2006; 98: 1546-1557Crossref PubMed Scopus (80) Google Scholar and some evaluated in early clinical trials.7Markert JM Medlock MD Rabkin SD Gillespie GY Todo T Hunter WD et al.Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial.Gene Ther. 2000; 7: 867-874Crossref PubMed Scopus (810) Google Scholar,8Chiocca EA Abbed KM Tatter S Louis DN Hochberg FH Barker F et al.A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting.Mol Ther. 2004; 10: 958-966Abstract PubMed Scopus Google JM E E et trial of oncolytic virus in recurrent Ther. 2006; PubMed Scopus Google P D C Morris D et al.A phase I trial of administration of in with recurrent malignant Ther. PubMed Scopus Google S J R R M et injection into the brain to of glioma: and Ther. 2004; PubMed Scopus Google R M R D J et potential for efficacy of the herpes simplex virus injection into human malignant glioma: a of Ther. PubMed Scopus Google EA trial of oncolytic herpes virus G207 of and viral Ther. PubMed Scopus Google JM W S E M et trial of mutant herpes simplex virus G207 for recurrent Ther. PubMed Scopus Google Scholar These found that therapy is with a few more OVs be found for the treatment of virus (VV) is a virus with a for several over other as is to replication and are is into and is in models and JW J et al.A recombinant vaccinia virus human and in a J PubMed Scopus Google A JM JM a and and PubMed Scopus Google Scholar is clinical with as a for are PM therapy targeting and in Ther. 7: PubMed Scopus Google T et of a oncolytic in with primary a phase I PubMed Scopus Google of replicating have efficacy in preclinical MG J D et effect of vaccinia virus in glioma Res. Google H R et of administered oncolytic vaccinia for malignant is by combination therapy with rapamycin Cancer Res. PubMed Scopus Google Scholar and other M Lee J et the replicating oncolytic effect and the effect of tumor Ther. 2000; 7: PubMed Scopus Google Lee et oncolytic and therapy for with a Ther. 2006; PubMed Scopus Google E RL et of human tumors in with an intravenously oncolytic vaccinia Res. PubMed Scopus Google I et virus and human and murine tumors in Ther. PubMed Scopus Google H E R et for a vaccinia PubMed Scopus Google Scholar potential of a replicating a mutant and vaccinia growth factor of the was to several tumor in murine models significant JM Lee J et therapy with a vaccinia virus mutant and vaccinia growth factor Res. 2001; Google Scholar is administered intravenously in nonhuman S H et and delivery of and a replicating mutant vaccinia virus in nonhuman Ther. 2006; PubMed Scopus Google Scholar and in rodent MG H R et of administered oncolytic vaccinia for malignant is by combination therapy with rapamycin Cancer Res. PubMed Scopus Google Scholar a potential for is a and oncolytic by of human granulocyte macrophage colony-stimulating factor and of by of into the viral Lee et oncolytic and therapy for with a Ther. 2006; PubMed Scopus Google Scholar murine than human and is in rodent models rodents to human These are to in cells with and growth factor pathway Lee et oncolytic and therapy for with a Ther. 2006; PubMed Scopus Google Scholar JX-594 efficacy in preclinical T J The oncolytic JX-594 and in with Ther. PubMed Scopus Google Scholar and a phase I trial of (i.t.) JX-594 in found significant antitumor with viral replication and of the T et of a oncolytic in with primary a phase I PubMed Scopus Google of this study to investigate the efficacy and safety/toxicity of JX-594 and administered in immunocompetent rodent and human brain tumor-initiating cells

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