SummaryObjectives In recent years, the incidence of Human Papilloma Virus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) has markedly increased. Our aim was to design a novel therapeutic agent through the use of conditionally replicative adenoviruses (CRAds) that are targeted to the HPV E6 and E7 oncoproteins. Methods Each adenovirus included small deletion(s) in the E1a region of the genome (Δ24 or CB016) intended to allow for selective replication in HPV-positive cells. In vitro assays were performed to analyze the transduction efficiency of the vectors and the cell viability following viral infection. Then, the UPCI SCC090 cell line (HPV-positive) was used to establish subcutaneous tumors in the flanks of nude mice. The tumors were then treated with either one dose of the virus or four doses (injected every fourth day). Results The transduction analysis with luciferase-expressing viruses demonstrated that the 5/3 fiber modification maximized virus infectivity. In vitro, both viruses (5/3Δ24 and 5/3CB016) demonstrated profound oncolytic effects. The 5/3CB016 virus was more selective for HPV-positive HNSCC cells, whereas the 5/3Δ24 virus killed HNSCC cells regardless of HPV status. In vivo, single injections of both viruses demonstrated anti-tumor effects for only a few days following viral inoculation. However, after four viral injections, there was statistically significant reductions in tumor growth when compared to the control group (p < 0.05). Conclusion CRAds targeted to HPV-positive HNSCCs demonstrated excellent in vitro and in vivo therapeutic effects, and they have the potential to be clinically translated as a novel treatment modality for this emerging disease.
|Original language||English (US)|
|Number of pages||7|
|State||Published - May 1 2016|
Bibliographical noteFunding Information:
The project was partly funded by NIH grants R01CA168448 (MY), R01CA196215 (MY), and R01CA174861 (JD), as well as a University of Minnesota Academic Health Center Faculty Research Development Grant (MY, MH, RG). Additional funding was provided by a VFW Surgical Oncology Research Grant (CL). We are grateful to Drs. Ramon Alemany and Cristina Balagué for providing the plasmids encoding the CB016 and D24 mutations.
The project was partly funded by NIH grants R01CA168448 (MY), R01CA196215 (MY), and R01CA174861 (JD), as well as a University of Minnesota Academic Health Center Faculty Research Development Grant (MY, MH, RG). Additional funding was provided by a VFW Surgical Oncology Research Grant (CL).
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