Don Morris

A Phase I Trial of Intratumoral Administration of Reovirus in Patients With Histologically Confirmed Recurrent Malignant Gliomas

Peter Forsyth, Glòria Roldán, David H. George et al.|Molecular Therapy|2008

Cited by 279Open Access

Reovirus is an oncolytic virus with activity in in vivo models of malignant gliomas (MGs). The primary aims were to determine the dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD) of intratumoral administration of reovirus in patients with recurrent MGs. Response, survival, and time to progression (TTP) were secondary aims. Patients were adults, had Karnofsky Performance score ≥ 60, received prior radiotherapy with or without chemotherapy, and had up to the third recurrence of MG. Reovirus was administered intratumorally stereotactically at 1 × 107, 1 × 108, or 1 × 109 tissue culture infectious dose 50 (TCID50) in a volume of 0.9 ml. Twelve patients were treated at three dose levels (3, 6, and 3 patients, respectively). Seven were men, median Karnofsky Performance score was 80, and median age was 53.5 years. There were no grade III or IV adverse events (AEs) definitely or probably related to treatment. Ten patients had tumor progression, one had stabilization, and one was not evaluable for response. Median survival was 21 weeks (range, 6–234), and one is alive 54 months after treatment. Median TTP was 4.3 weeks (range, 2.6–39). An MTD was not reached. The intratumoral administration of the genetically unmodified reovirus was well tolerated using these doses and schedule, in patients with recurrent MG. Reovirus is an oncolytic virus with activity in in vivo models of malignant gliomas (MGs). The primary aims were to determine the dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD) of intratumoral administration of reovirus in patients with recurrent MGs. Response, survival, and time to progression (TTP) were secondary aims. Patients were adults, had Karnofsky Performance score ≥ 60, received prior radiotherapy with or without chemotherapy, and had up to the third recurrence of MG. Reovirus was administered intratumorally stereotactically at 1 × 107, 1 × 108, or 1 × 109 tissue culture infectious dose 50 (TCID50) in a volume of 0.9 ml. Twelve patients were treated at three dose levels (3, 6, and 3 patients, respectively). Seven were men, median Karnofsky Performance score was 80, and median age was 53.5 years. There were no grade III or IV adverse events (AEs) definitely or probably related to treatment. Ten patients had tumor progression, one had stabilization, and one was not evaluable for response. Median survival was 21 weeks (range, 6–234), and one is alive 54 months after treatment. Median TTP was 4.3 weeks (range, 2.6–39). An MTD was not reached. The intratumoral administration of the genetically unmodified reovirus was well tolerated using these doses and schedule, in patients with recurrent MG. IntroductionThe current treatments for patients with malignant gliomas (MGs) are inadequate: The median survival for patients with glioblastoma multiforme (GBM), the most common MG, is only ∼1 year. Therefore, novel treatment strategies are needed. A number of replication‐competent oncolytic viruses have been selected or engineered as novel therapeutics for cancer.1Gromeier M Wimmer E Viruses for the treatment of malignant glioma.Curr Opin Mol Ther. 2001; 3: 503-508PubMed Google Scholar,2Parato KA Senger D Forsyth PA Bell JC Recent progress in the battle between oncolytic viruses and tumours.Nat Rev Cancer. 2005; 5: 965-976Crossref PubMed Scopus (449) Google Scholar These viruses selectively infect and kill tumor cells but leave normal cells unaffected (or relatively so) by exploiting genetic defects that are unique to tumor cells. For several oncolytic viruses (e.g., reovirus, herpes simplex virus, vesicular stomatitis virus) tumor cells have defects in a number of antiviral pathways, which render them susceptible to viral infection. Approximately 20 oncolytic viruses are being tested in clinical trials for a variety of cancers.2Parato KA Senger D Forsyth PA Bell JC Recent progress in the battle between oncolytic viruses and tumours.Nat Rev Cancer. 2005; 5: 965-976Crossref PubMed Scopus (449) Google Scholar For recurrent MGs in particular,3Shah AC Benos D Gillespie GY Markert JM Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas.J Neurooncol. 2003; 65: 203-226Crossref PubMed Scopus (108) Google Scholar clinical trials using herpes simplex virus,4Markert 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,5Rampling R Cruickshank G Papanastassiou V Nicoll J Hadley D Brennan D et al.Toxicity evaluation of replication‐competent herpes simplex virus (ICP null mutant 1716) in patients with recurrent malignant gliomas.Gene Ther. 2000; 7: 859-866Crossref PubMed Scopus (516) Google Scholar,6Papanastassiou V Rampling R Fraser M Petty R Hadley D Nicoll J et al.The potential for efficacy of the modified (ICP 34.5(–)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study.Gene Ther. 2002; 9: 398-406Crossref PubMed Scopus (272) Google Scholar,7Harrow S Papanastassiou V Harland J Mabbs R Petty R Fraser M et al.HSV1716 injection into the brain adjacent to tumour following surgical resection of high‐grade glioma: safety data and long‐term survival.Gene Ther. 2004; 11: 1648-1658Crossref PubMed Scopus (278) Google Scholar Newcastle disease virus,8Csatary LK Gosztonyi G Szeberenyi J Fabian Z Liszka V Bodey B et al.MTH‐68/H oncolytic viral treatment in human high‐grade gliomas.J Neurooncol. 2004; 67: 83-93Crossref PubMed Scopus (152) Google Scholar,9Freeman AI Zakay‐Rones Z Gomori JM Linetsky E Rasooly L Greenbaum E et al.Phase I/II trial of intravenous NDV‐HUJ oncolytic virus in recurrent glioblastoma multiforme.Mol Ther. 2006; 13: 221-228Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar and adenovirus10Chiocca EA Abbed KM Tatter S Lous DN Hochberg FH Barker F et al.A phase 1 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 Full Text Full Text PDF PubMed Scopus (331) Google Scholar have been reported; trials using measles virus, poliovirus, and vaccinia virus are planned/in progress.We discovered that reovirus (respiratory enteric orphan), a double‐stranded RNA virus commonly isolated from the respiratory and gastrointestinal tracts of humans, infects and lyses cells but not normal J M D et al.The of viral of the by PubMed Scopus (449) Google Forsyth PA Reovirus of with PubMed Scopus Google T A Senger et is a for reovirus Ther. Full Text Full Text PDF PubMed Scopus Google Senger D et as an oncolytic human malignant gliomas.J 2001; PubMed Scopus Google T A Oncolytic reovirus and 2002; Google et reovirus of in 2003; Google Scholar Reovirus not disease in as but a in Scholar and B JM IV and are not for 67: Google Scholar Reovirus the (or of tumor cells to viral and malignant tumor cells with J M D et al.The of viral of the by PubMed Scopus (449) Google Forsyth PA Reovirus of with PubMed Scopus Google T A Senger et is a for reovirus Ther. Full Text Full Text PDF PubMed Scopus Google Scholar efficacy Forsyth PA Reovirus of with PubMed Scopus Google 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 Senger D D et survival and the of and from 2003; Google Senger et as an for brain and from Ther. 2004; 11: PubMed Scopus Google et and safety evaluation of human reovirus 3 in and 2004; 10: PubMed Scopus Google Scholar of brain administration into the of was well et and safety evaluation of human reovirus 3 in and 2004; 10: PubMed Scopus Google Scholar A number of phase I have been Forsyth PA et al.A phase 1 clinical trial in 2002; 21 L J L M et al.A phase I of reovirus, which selectively in cells administered to patients with 2006; Full Text PDF Google L M et al.A phase I trial of intratumoral administration of reovirus 3 in with in patients with 2006; R I B M et and safety of in patients with Scholar the administration of reovirus intratumorally or in with in patients with from intratumorally in patients with and in patients with These no in of the treated patients, and a maximum tolerated dose (MTD) been of were to determine the safety of the intratumoral administration of doses of clinical trials have administered herpes simplex 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,5Rampling R Cruickshank G Papanastassiou V Nicoll J Hadley D Brennan D et al.Toxicity evaluation of replication‐competent herpes simplex virus (ICP null mutant 1716) in patients with recurrent malignant gliomas.Gene Ther. 2000; 7: 859-866Crossref PubMed Scopus (516) Google Scholar,6Papanastassiou V Rampling R Fraser M Petty R Hadley D Nicoll J et al.The potential for efficacy of the modified (ICP 34.5(–)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study.Gene Ther. 2002; 9: 398-406Crossref PubMed Scopus (272) Google Scholar,7Harrow S Papanastassiou V Harland J Mabbs R Petty R Fraser M et al.HSV1716 injection into the brain adjacent to tumour following surgical resection of high‐grade glioma: safety data and long‐term survival.Gene Ther. 2004; 11: 1648-1658Crossref PubMed Scopus (278) Google Scholar or adenovirus10Chiocca EA Abbed KM Tatter S Lous DN Hochberg FH Barker F et al.A phase 1 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 Full Text Full Text PDF PubMed Scopus (331) Google Scholar into the of patients with recurrent is the that the administration of a genetically unmodified virus, using these is and well patients were from to The median age was 53.5 to the administration of reovirus patients had a of had and one had an Median Karnofsky score was treatment was administered for the or third recurrence in and one The median time between the of an and reovirus administration was months patients received radiotherapy and received of patients with recurrent malignant gliomas treated with not up to one to at of brain tumor grade of recurrence prior to Reovirus administration at (TCID50) at Karnofsky Performance tissue culture infectious dose not up to one to in a and most common adverse was a of related to tumor progression and not related to viral administration in III or and to viral administration are in The in the × tissue culture infectious dose 50 recurrent weeks after reovirus administration related to with The was related to to the the of the had grade III of and grade IV related to the viral with adverse events to in a the dose × the was to the for and after reovirus The a grade III which was related to viral infection. The third in and after reovirus administration of was to the for and The a and a grade III to the of the three patients with a of were at that dose and had a dose‐limiting toxicity to the third dose × 109 the MTD was not reached. of the at 1 × 109 was definitely or probably related to the administration of patients had tumor at following injection with related to the had a with and a of were at and and viral for the patients were by Ten patients for from 1 to weeks after viral had for the time and × × × × had not been for × × × × and × at × × × after intratumoral viral not the had not been for in a was by in and using the for RNA was not in the or of from the was in one and in the from of was at but after viral viral RNA in was and and in had viral RNA in and had had and one was not evaluable for had a at and had is alive 54 months after viral treatment For the as a the median time to progression (TTP) was 4.3 weeks 2.6–39). The median survival was 21 weeks patients for and three patients for of these had a recurrent and of recurrent one is alive at 54 months after treatment with of patients treated with at × × × × × × × × × × × × glioblastoma not grade time to in a of tumor tissue after reovirus of the patients had from 3 to 20 after the intratumoral viral treatment 6, and had or recurrent and of in three of the patients of cells were at the time of that were not in the prior to the administration of and was as related to reovirus treatment. patients, of normal brain were and was no of had with the of a that was but in cells at the time of after reovirus was in three had had been with a had of tumor at and was with a grade There was no of in of is that the administration of reovirus into the of patients with MGs was well tolerated and at the doses and is the of a and genetically unmodified virus administered into the brain of clinical trials of oncolytic viruses administered have viruses that are or by genetic 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,5Rampling R Cruickshank G Papanastassiou V Nicoll J Hadley D Brennan D et al.Toxicity evaluation of replication‐competent herpes simplex virus (ICP null mutant 1716) in patients with recurrent malignant gliomas.Gene Ther. 2000; 7: 859-866Crossref PubMed Scopus (516) Google Scholar,6Papanastassiou V Rampling R Fraser M Petty R Hadley D Nicoll J et al.The potential for efficacy of the modified (ICP 34.5(–)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study.Gene Ther. 2002; 9: 398-406Crossref PubMed Scopus (272) Google EA Abbed KM Tatter S Lous DN Hochberg FH Barker F et al.A phase 1 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 Full Text Full Text PDF PubMed Scopus (331) Google E JC et al.Phase 1 of of the and administration in patients with recurrent malignant Ther. 2000; Full Text Full Text PDF PubMed Scopus Google M J M of malignant with an the herpes simplex by Ther. 2003; 7: Full Text Full Text PDF PubMed Scopus Google JM MD S et al.Phase I trial of for recurrent glioma: and clinical 2003; PubMed Scopus Google Scholar in these no dose‐limiting at the (e.g., 3 × 109 for herpes simplex 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 was in trials in which a virus was administered into the brain adjacent to the S Papanastassiou V Harland J Mabbs R Petty R Fraser M et al.HSV1716 injection into the brain adjacent to tumour following surgical resection of high‐grade glioma: safety data and long‐term survival.Gene Ther. 2004; 11: 1648-1658Crossref PubMed Scopus (278) Google EA Abbed KM Tatter S Lous DN Hochberg FH Barker F et al.A phase 1 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 Full Text Full Text PDF PubMed Scopus (331) Google Scholar The of oncolytic viruses in brain is viral in the no of or viral was The of but no had clinical of which a was not to efficacy as a primary Patients were not with to number of treatment or tumor and have for the evaluation of as viruses that of tumor after treatment. patients had following treatment with reovirus and one a long‐term a treatment trials using oncolytic viruses long‐term 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,5Rampling R Cruickshank G Papanastassiou V Nicoll J Hadley D Brennan D et al.Toxicity evaluation of replication‐competent herpes simplex virus (ICP null mutant 1716) in patients with recurrent malignant gliomas.Gene Ther. 2000; 7: 859-866Crossref PubMed Scopus (516) Google Scholar or patients have no of recurrent 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 a of with clinical using L J L M et al.A phase I of reovirus, which selectively in cells administered to patients with 2006; Full Text PDF Google Scholar is in trials with oncolytic viruses to safety from by and There was of using in the of one and in the from patients, of which was of viral but not was not the A of is that was after using only three of the dose levels to patients, and after patients were treated at the third dose the of the virus not A is in patients with recurrent MGs using a of at which a intratumoral and is to to a viral dose using a volume the current was not to determine was of viral or the phase I with administration of reovirus, reovirus had been from tumor L J L M et al.A phase I of reovirus, which selectively in cells administered to patients with 2006; Full Text PDF Google Scholar and virus and have been in tumor using tumor tissue in patients at following reovirus administration was but viral culture or were not these were had and were at after viral intratumoral viral viral or the of these of and clinical to intratumoral with viral were of oncolytic viruses of viral for tumor evaluation of and of viral the for administration into tumor that not to treatment or were not D by herpes simplex virus and Ther. 2005; PubMed Scopus Google clinical trial that the intratumoral administration of genetically unmodified reovirus in patients with MGs up to a dose of 1 × 109 was and well to determine efficacy and the of administration are and and The primary of trial was to determine the and MTD of administration for reovirus in patients with and evaluable recurrent MG. of survival at and TTP were secondary Patients with a Karnofsky score and a or recurrent with a of weeks were disease was by with an of but which was for administration of virus without the or was by a and of recurrence was prior to the administration of patients had been treated with and with or without chemotherapy, and had a to third Patients had and of potential had a Patients were patients a dose of and was at the of the prior brain or radiotherapy weeks or in the viral or antiviral prior to was in with of the of and The and patients were to and the phase I reovirus was to to the of toxicity or a maximum dose of 1 × The volume of viral injection was 0.9 and 1 × 107, 1 × 108, and 1 × 109 in of the dose levels three patients were in dose There was following the in and between The were the three patients with were in the to the phase received a viral administration of into of three adjacent 0.9 the tumor stereotactically using a clinical and evaluation were weeks prior to viral administration and at weeks for The D V of and of Google Scholar was to determine patients for at of for weeks and time and of levels Patients and without weeks of and the as viral of viral in of and to viral RNA was using virus from of was with one in using a as and for a volume of of of of of of 1 of and of RNA were were as at 50 for at for of at at and for at and of at of viral was by in to reovirus a for the of reovirus in human the of by infectious were to of cells at was and the was with a at a and for to and for in culture into that the of the the of human that reovirus were and from one to were in with in to an in a was an in at a the of a was at the of the or at and were to the of was as grade III or IV toxicity or probably related to the a was in one of three patients at a dose a three patients were to in that patients in the dose was to the for tumor was of weeks and weeks were using for phase of malignant PubMed Scopus Google were TTP and survival were from the time of viral IntroductionThe current treatments for patients with malignant gliomas (MGs) are inadequate: The median survival for patients with glioblastoma multiforme (GBM), the most common MG, is only ∼1 year. Therefore, novel treatment strategies are needed. A number of replication‐competent oncolytic viruses have been selected or engineered as novel therapeutics for cancer.1Gromeier M Wimmer E Viruses for the treatment of malignant glioma.Curr Opin Mol Ther. 2001; 3: 503-508PubMed Google Scholar,2Parato KA Senger D Forsyth PA Bell JC Recent progress in the battle between oncolytic viruses and tumours.Nat Rev Cancer. 2005; 5: 965-976Crossref PubMed Scopus (449) Google Scholar These viruses selectively infect and kill tumor cells but leave normal cells unaffected (or relatively so) by exploiting genetic defects that are unique to tumor cells. For several oncolytic viruses (e.g., reovirus, herpes simplex virus, vesicular stomatitis virus) tumor cells have defects in a number of antiviral pathways, which render them susceptible to viral infection. Approximately 20 oncolytic viruses are being tested in clinical trials for a variety of cancers.2Parato KA Senger D Forsyth PA Bell JC Recent progress in the battle between oncolytic viruses and tumours.Nat Rev Cancer. 2005; 5: 965-976Crossref PubMed Scopus (449) Google Scholar For recurrent MGs in particular,3Shah AC Benos D Gillespie GY Markert JM Oncolytic viruses: clinical applications as vectors for the treatment of malignant gliomas.J Neurooncol. 2003; 65: 203-226Crossref PubMed Scopus (108) Google Scholar clinical trials using herpes simplex virus,4Markert 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,5Rampling R Cruickshank G Papanastassiou V Nicoll J Hadley D Brennan D et al.Toxicity evaluation of replication‐competent herpes simplex virus (ICP null mutant 1716) in patients with recurrent malignant gliomas.Gene Ther. 2000; 7: 859-866Crossref PubMed Scopus (516) Google Scholar,6Papanastassiou V Rampling R Fraser M Petty R Hadley D Nicoll J et al.The potential for efficacy of the modified (ICP 34.5(–)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study.Gene Ther. 2002; 9: 398-406Crossref PubMed Scopus (272) Google Scholar,7Harrow S Papanastassiou V Harland J Mabbs R Petty R Fraser M et al.HSV1716 injection into the brain adjacent to tumour following surgical resection of high‐grade glioma: safety data and long‐term survival.Gene Ther. 2004; 11: 1648-1658Crossref PubMed Scopus (278) Google Scholar Newcastle disease virus,8Csatary LK Gosztonyi G Szeberenyi J Fabian Z Liszka V Bodey B et al.MTH‐68/H oncolytic viral treatment in human high‐grade gliomas.J Neurooncol. 2004; 67: 83-93Crossref PubMed Scopus (152) Google Scholar,9Freeman AI Zakay‐Rones Z Gomori JM Linetsky E Rasooly L Greenbaum E et al.Phase I/II trial of intravenous NDV‐HUJ oncolytic virus in recurrent glioblastoma multiforme.Mol Ther. 2006; 13: 221-228Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar and adenovirus10Chiocca EA Abbed KM Tatter S Lous DN Hochberg FH Barker F et al.A phase 1 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 Full Text Full Text PDF PubMed Scopus (331) Google Scholar have been reported; trials using measles virus, poliovirus, and vaccinia virus are planned/in progress.We discovered that reovirus (respiratory enteric orphan), a double‐stranded RNA virus commonly isolated from the respiratory and gastrointestinal tracts of humans, infects and lyses cells but not normal J M D et al.The of viral of the by PubMed Scopus (449) Google Forsyth PA Reovirus of with PubMed Scopus Google T A Senger et is a for reovirus Ther. Full Text Full Text PDF PubMed Scopus Google Senger D et as an oncolytic human malignant gliomas.J 2001; PubMed Scopus Google T A Oncolytic reovirus and 2002; Google et reovirus of in 2003; Google Scholar Reovirus not disease in as but a in Scholar and B JM IV and are not for 67: Google Scholar Reovirus the (or of tumor cells to viral and malignant tumor cells with J M D et al.The of viral of the by PubMed Scopus (449) Google Forsyth PA Reovirus of with PubMed Scopus Google T A Senger et is a for reovirus Ther. Full Text Full Text PDF PubMed Scopus Google Scholar efficacy Forsyth PA Reovirus of with PubMed Scopus Google 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 Senger D D et survival and the of and from 2003; Google Senger et as an for brain and from Ther. 2004; 11: PubMed Scopus Google et and safety evaluation of human reovirus 3 in and 2004; 10: PubMed Scopus Google Scholar of brain administration into the of was well et and safety evaluation of human reovirus 3 in and 2004; 10: PubMed Scopus Google Scholar A number of phase I have been Forsyth PA et al.A phase 1 clinical trial in 2002; 21 L J L M et al.A phase I of reovirus, which selectively in cells administered to patients with 2006; Full Text PDF Google L M et al.A phase I trial of intratumoral administration of reovirus 3 in with in patients with 2006; R I B M et and safety of in patients with Scholar the administration of reovirus intratumorally or in with in patients with from intratumorally in patients with and in patients with These no in of the treated patients, and a maximum tolerated dose (MTD) been of were to determine the safety of the intratumoral administration of doses of clinical trials have administered herpes simplex 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,5Rampling R Cruickshank G Papanastassiou V Nicoll J Hadley D Brennan D et al.Toxicity evaluation of replication‐competent herpes simplex virus (ICP null mutant 1716) in patients with recurrent malignant gliomas.Gene Ther. 2000; 7: 859-866Crossref PubMed Scopus (516) Google Scholar,6Papanastassiou V Rampling R Fraser M Petty R Hadley D Nicoll J et al.The potential for efficacy of the modified (ICP 34.5(–)) herpes simplex virus HSV1716 following intratumoural injection into human malignant glioma: a proof of principle study.Gene Ther. 2002; 9: 398-406Crossref PubMed Scopus (272) Google Scholar,7Harrow S Papanastassiou V Harland J Mabbs R Petty R Fraser M et al.HSV1716 injection into the brain adjacent to tumour following surgical resection of high‐grade glioma: safety data and long‐term survival.Gene Ther. 2004; 11: 1648-1658Crossref PubMed Scopus (278) Google Scholar or adenovirus10Chiocca EA Abbed KM Tatter S Lous DN Hochberg FH Barker F et al.A phase 1 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 Full Text Full Text PDF PubMed Scopus (331) Google Scholar into the of patients with recurrent is the that the administration of a genetically unmodified virus, using these is and well

Reovirus as an Oncolytic Agent Against Experimental Human Malignant Gliomas

M. Elizabeth Wilcox, Wenqing Yang, Donna L. Senger et al.|JNCI Journal of the National Cancer Institute|2001

Cited by 219

BACKGROUND: Reovirus is a naturally occurring oncolytic virus that usurps activated Ras-signaling pathways of tumor cells for its replication. Ras pathways are activated in most malignant gliomas via upstream signaling by receptor tyrosine kinases. The purpose of this study was to determine the effectiveness of reovirus as an experimental treatment for malignant gliomas. METHODS: We investigated whether reovirus would infect and lyse human glioma cell lines in vitro. We also tested the effect of injecting live reovirus in vivo on human gliomas grown subcutaneously or orthotopically (i.e., intracerebrally) in mice. Finally, reovirus was tested ex vivo against low-passage cell lines derived from human glioma specimens. All P values were two-sided. RESULTS: Reovirus killed 20 (83%) of 24 established malignant glioma cell lines tested. It caused a dramatic and often complete tumor regression in vivo in two subcutaneous (P =.0002 for both U251N and U87) and in two intracerebral (P =.0004 for U251N and P =.0009 for U87) human malignant glioma mouse models. As expected, serious toxic effects were found in these severely immunocompromised hosts. In a less immunocompromised mouse model, a single intratumoral inoculation of live reovirus led to a dramatic prolongation of survival (compared with control mice treated with dead virus; log-rank test, P<.0001 for both U251N and U87 cell lines). The animals treated with live virus also appeared to be healthier and gained body weight (P =.0001). We then tested the ability of reovirus to infect and kill primary cultures of brain tumors removed from patients and found that it killed nine (100%) of nine glioma specimens but none of the cultured meningiomas. CONCLUSIONS: Reovirus has potent activity against human malignant gliomas in vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.

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