title: Immunocompetent syngeneic cotton rat tumor models for the assessment of replication-competent oncolytic adenovirus.
abstract: Oncolytic adenoviruses as a treatment for cancer have demonstrated limited clinical activity. Contributing to this may be the relevance of preclinical animal models used to study these agents. Syngeneic mouse tumor models are generally non-permissive for adenoviral replication, whereas human tumor xenograft models exhibit attenuated immune responses to the vector. The cotton rat (Sigmodon hispidus) is susceptible to human adenovirus infection, permissive for viral replication and exhibits similar inflammatory pathology to humans with adenovirus replicating in the lungs, respiratory passages and cornea. We evaluated three transplantable tumorigenic cotton rat cell lines, CCRT, LCRT and VCRT as models for the study of oncolytic adenoviruses. All three cells lines were readily infected with adenovirus type-5-based vectors and exhibited high levels of transgene expression. The cell lines supported viral replication demonstrated by the induction of cytopathogenic effect (CPE) in tissue culture, increase in virus particle numbers and assembly of virions seen on transmission electron microscopy. In vivo, LCRT and VCRT tumors demonstrated delayed growth after injection with replicating adenovirus. No in vivo antitumor activity was seen in CCRT tumors despite in vitro oncolysis. Adenovirus was also rapidly cleared from the CCRT tumors compared to LCRT and VCRT tumors. The effect observed with the different cotton rat tumor cell lines mimics the variable results of human clinical trials highlighting the potential relevance of this model for assessing the activity and toxicity of oncolytic adenoviruses.
authors.affiliation: Cancer Gene Therapy Section, Metabolism Branch, Center for Cancer Research, National Cancer Institute, Mark O. Hatfield Clinical Research Center, Room 4-5330, 10 Center Drive, Bethesda, MD 20892-1457, National Institutes of Health, Maryland, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Steel
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morrison
authors.forename: Poonam
authors.initials: P
authors.lastname: Mannan
authors.forename: Mones S
authors.initials: MS
authors.lastname: Abu-Asab
authors.forename: Oliver
authors.initials: O
authors.lastname: Wildner
authors.forename: Brian K
authors.initials: BK
authors.lastname: Miles
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Yim
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramanan
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Prince
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
mesh_terms: D000256:Adenoviridae / Q000254:growth & development*; D000818:Animals; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D004195:Disease Models, Animal; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000628:therapy* / Q000821:virology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D051381:Rats; D016205:Sigmodontinae; D014185:Transplantation, Isogeneic; D010948:Viral Plaque Assay; D014771:Virion / Q000648:ultrastructure