title: Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma.
abstract: Rhabdomyosarcoma (RMS), a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV), are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS) and alveolar rhabdomyosarcoma (ARMS) cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Waters
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Stafman
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: Evan F
authors.initials: EF
authors.lastname: Garner
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: Smitha
authors.initials: S
authors.lastname: Mruthyunjayappa
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: Jerry E
authors.initials: JE
authors.lastname: Stewart
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Friedman
authors.affiliation: Department of Surgery, Division of Neurosurgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Coleman
authors.affiliation: Department of Surgery, Division of Neurosurgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: James M
authors.initials: JM
authors.lastname: Markert
authors.affiliation: Department of Surgery, Division of Neurosurgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233.
authors.forename: G Yancey
authors.initials: GY
authors.lastname: Gillespie
authors.affiliation: Department of Surgery, Division of Pediatric Surgery, University of Alabama, Birmingham, Birmingham, AL, USA 35233. Electronic address: elizabeth.beierle@childrensal.org.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Beierle