Preclinical evaluation of the therapeutic effect of adenoviral vectors in human papillomavirus-dependent neoplasias.

Gene therapy with adenoviral vectors can eliminate neoplasic cells through selective replication and/or through pro-apoptotic, immunogenic or suicide gene expression. However, an adenoviral vector may provide anti-cancerous effects even in the absence of replication or therapeutic gene expression. The present study evaluates the therapeutic effects caused by the administration of an adenoviral vector, alone, in HPV-dependent neoplasias (HPV-N). In vivo trials were carried out in two HPV-N mouse models. One model was immunocompetent and the other was immunodeficient. In both models, the effect of intratumoral administration of saline solution (PBS) was compared with administration of an adenoviral vector that had no replicative capacity or therapeutic gene (Ad-BGal). In the immunocompetent mice, Ad-BGal adenoviral vector administration significantly reduced tumor growth, compared with PBS. No differences were observed in the immunodeficient mice. In conclusion, the present study lends support to the use of adenoviral vectors in HPV-N treatment since they are capable of generating an antitumoral effect in immunocompetent individuals, even in the absence of a therapeutic gene or viral vector replication.

A potent replicative delta-24 adenoviral vector driven by the promoter of human papillomavirus 16 that is highly selective for associated neoplasms.

BACKGROUND: Several human epithelial neoplasms are associated with high-risk strains of human papillomavirus (HPV) such as cervical, anorectal, and other carcinomas. For some tumor types the current therapeutic tools are only palliative. Conditionally replicative adenoviruses (CRAds) are promising antineoplastic agents, which also can trigger confined antitumor effects. METHODS: We constructed a series of CRAds driven by the upstream regulatory promoter region (URR) of an Asian-American variant of HPV-16, which contained different mutations at the E1A region (dl1015 and/or Delta24) and wild-type. All vectors were tested in vitro for viral replication and cytotoxicity. Viral DNA replication and E1A expression were also assessed by quantitative PCR. Finally, we confirmed the antitumoral efficacy of this vector in injected and non-injected xenotransplanted cervical tumors in a murine model for tumor regression and survival studies. RESULTS: A vector denominated Ad-URR/E1ADelta24 displayed a potent cytopathic effect associated with high selectivity for HPV+ cell lines. We found that the oncolytic effect of this CRAd was comparable to Ad-wt or Ad-Delta24, but this efficacy was significantly attenuated in HPV- cell lines, an effect that was contributed by the URR promoter. Ad-URR/E1ADelta24 was very effective to control tumor growth, in both, injected and non-injected tumors generated with two different HPV+ cell lines. CONCLUSIONS: CRAd Ad-URR/E1ADelta24 is a highly selective vector for HPV+ cell lines and tumors that preserves the oncolytic efficacy of Ad-wt and Ad-Delta24. Our preclinical data suggest that this vector may be useful and safe for the treatment of tumors induced by HPV, like cervical cancers.