A conditionally replicating adenovirus for nasopharyngeal carcinoma gene therapy.
Successful attainment of tumor-specific gene expression was achieved in nasopharyngeal carcinoma (NPC) by exploiting the exclusive presence of the Epstein-Barr virus (EBV) genome in the cancer cells. In the current study, we have utilized an EBV-dependent transcriptional targeting strategy to construct a novel conditionally replicating adenovirus, adv.oriP.E1A. After treatment with adv.oriP.E1A, we observed extensive cell death in the EBV-positive NPC cell line C666-1. In contrast, no cytotoxicity was observed in a panel of other human EBV-negative cell lines, including fibroblasts from the nasopharynx. In vitro adenoviral replication was confirmed by the time-dependent increase in the expression of adenoviral capsid fiber protein and adenoviral DNA after C666-1 cells were infected with adv.oriP.E1A. Tumor formation was inhibited for more than 100 days after ex vivo infection of C666-1 cells with adv.oriP.E1A. Combination of local tumor radiation and adv.oriP.E1A caused complete disappearance of established tumors for at least 2 weeks in two distinct EBV-positive NPC xenograft models. Safety of this treatment was determined through the systemic delivery of adv.oriP.E1A in vivo, whereby minimal temporary perturbation of liver function was observed. We have successfully established a conditionally replicating adenovirus for EBV-positive NPC, which is both safe and efficacious, indicating a strategy that may be therapeutically applicable.
Chia
Marie C
MC
Division of Experimental Therapeutics, Princess Margaret Hospital/Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada M5G 2M9.
Shi
Wei
W
Li
Jian-Hua
JH
Sanchez
Otto
O
Strathdee
Craig A
CA
Huang
Dolly
D
Busson
Pierre
P
Klamut
Henry J
HJ
Liu
Fei-Fei
FF
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics; D000818:Animals; D002277:Carcinoma / Q000628:therapy*; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral; D004261:DNA Replication; D015316:Genetic Therapy / Q000379:methods*; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009303:Nasopharyngeal Neoplasms / Q000628:therapy*; D013154:Spleen / Q000473:pathology; D014779:Virus Replication / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D017500:Adenovirus E1A Proteins