A canine conditionally replicating adenovirus for evaluating oncolytic virotherapy in a syngeneic animal model.
Oncolytic adenoviruses, which selectively replicate in and subsequently kill cancer cells, have emerged as a promising approach for treatment of tumors resistant to other modalities. Although preclinical results have been exciting, single-agent clinical efficacy has been less impressive heretofore. The immunogenicity of adenoviruses, and consequent premature abrogation of replication, may have been a partial reason. Improving the oncolytic potency of agents has been hampered by the inability to study host-vector interactions in immune-competent systems, since human serotype adenoviruses do not productively replicate in animal tissues. Therefore, approaches such as immunomodulation, which could result in sustained replication and subsequently increased oncolysis, have not been studied. Utilizing the osteocalcin promoter for restricting the replication of a canine adenovirus to dog osteosarcoma cells, we generated and tested the first nonhuman oncolytic adenovirus. This virus effectively killed canine osteosarcoma cells in vitro and yielded a therapeutic benefit in vivo. Canine osteosarcoma is the most frequent malignant disease in large dogs, with over 8000 cases in the United States annually, and there is no curative treatment. Therefore, immunomodulation for increased oncolytic potency could be studied with clinical trials in this population. This could eventually translate into human trials.
Hemminki
Akseli
A
Division of Human Gene Therapy, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-2172, USA. Akseli.Hemminki@Helsinki.Fi
Kanerva
Anna
A
Kremer
Eric J
EJ
Bauerschmitz
Gerd J
GJ
Smith
Bruce F
BF
Liu
Bin
B
Wang
Minghui
M
Desmond
Renee A
RA
Keriel
Anne
A
Barnett
Brian
B
Baker
Henry J
HJ
Siegal
Gene P
GP
Curiel
David T
DT
D000256:Adenoviridae / Q000235:genetics*; D062705:Adenovirus Vaccines; D000818:Animals; D016923:Cell Death; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D015675:Osteocalcin / Q000235:genetics; D012516:Osteosarcoma / Q000628:therapy; D010957:Plasmids / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014761:Viral Hepatitis Vaccines / Q000235:genetics
D062705:Adenovirus Vaccines; D014761:Viral Hepatitis Vaccines; C042832:adenovirus type-2 vaccine (canine); D015675:Osteocalcin; D008156:Luciferases