Identifying the Safety Profile of Ad5.SSTR/TK.RGD, a Novel Infectivity-Enhanced Bicistronic Adenovirus, in Anticipation of a Phase I Clinical Trial in Patients with Recurrent Ovarian Cancer

Purpose: The purpose of this study was to evaluate the biodistribution and toxicity of Ad5.SSTR/TK.RGD, an infectivity-enhanced adenovirus expressing a therapeutic suicide gene and somatostatin receptor type 2 (for noninvasive assessment of gene transfer with nuclear imaging) in advance of a planned phase I clinical trial for recurrent ovarian carcinoma. Experimental Design: Cohorts of Syrian hamsters were treated i.p. for 3 consecutive days with Ad5.SSTR/TK.RGD or control buffer with or without the prodrug ganciclovir (GCV) and euthan- ized on day 4, 19, or 56. Tissue and serum samples were evaluated for the presence of virus using qPCR analysis and were assessed for vector-related tissue or laboratory effects. Results: Levels of Ad5.SSTR/TK.RGD in blood and tissues outside of the abdominal cavity were low, indicating minimal systemic absorption. GCV did not affect Ad5.SSTR/TK.RGD biodistribu- tion. The mean Ad5.SSTR/TK.RGD viral level was 100-fold lower on day 19 than day 4, suggest- ing vector elimination over time. Animals in the Ad5.SSTR/TK.RGD F GCV cohort had clinical laboratory parameters and microscopic lesions in the abdominal organs indicative of an inflamma- tory response. Toxicity in this dose cohort seemed to be reversible over time. Conclusions: These studies provide justification for planned dosing of Ad5.SSTR/TK.RGD for a planned phase I clinical trial and insights regarding anticipated toxicity.