Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses.
Natural and genetically modified oncolytic viruses have been systematically tested as anticancer therapeutics. Among this group, conditionally replicative adenoviruses have been developed for a broad range of tumors with a rapid transition to clinical settings. Unfortunately, clinical trials have shown limited antitumor efficacy partly due to insufficient viral delivery to tumor sites. We investigated the possibility of using mesenchymal progenitor cells (MPC) as virus carriers based on the documented tumor-homing abilities of this cell population. We confirmed preferential tumor homing of MPCs in an animal model of ovarian carcinoma and evaluated the capacity of MPCs to be loaded with oncolytic adenoviruses. We showed that MPCs were efficiently infected with an adenovirus genetically modified for coxsackie and adenovirus receptor-independent infection (Ad5/3), which replicated in the cell carriers. MPCs loaded with Ad5/3 caused total cell killing when cocultured with a cancer cell line. In an animal model of ovarian cancer, MPC-based delivery of the Ad5/3 increased the survival of tumor-bearing mice compared with direct viral injection. Further, tumor imaging confirmed a decrease in tumor burden in animals treated with oncolytic virus delivered by MPC carriers compared with the direct injection of the adenovirus. These data show that MPCs can serve as intermediate carriers for replicative adenoviruses and suggest that the natural homing properties of specific cell types can be used for targeted delivery of these virions.
Komarova
Svetlana
S
Division of Human Gene Therapy, Department of Medicine, Gene Therapy Center, University of Alabama at Birmingham, 901 19th Street South, BMR2-572, Birmingham, AL 35294-3300, USA.
Kawakami
Yosuke
Y
Stoff-Khalili
Mariam A
MA
Curiel
David T
DT
Pereboeva
Larisa
L
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D050504:Oncolytic Viruses / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000473:pathology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays