Oncolytic viral therapy by bladder instillation using an E1A, E1B double-restricted adenovirus in an orthotopic bladder cancer model

Objectives: To investigate the therapeutic effect of AxdAdB-3, a double-restricted oncolytic adenovirus harboring a mutant E1A and an E1B-55KD deletion, on human bladder cancer cell lines and the SCID mouse model of orthotopic bladder cancer. Methods: The cytopathic effects of AxdAdB-3 were evaluated in several cell lines (YTS-1, YTS-3, T24, J82, 5637) derived from human bladder or ureteral cancer and in a normal bladder mucosa-derived cell line (HCV29) with AxCAlacZ (control) or AxE1AdB (E1B-55KD-defective adenovirus) or dl922-947 (E1A-mutated adenovirus). The efficacy of bladder instillation therapy with AxdAdB-3 for orthotopic bladder cancer of SCID mice was investigated. The oncolytic effects were monitored by ultrasound examination. Results: AxdAdB-3 caused the oncolysis of bladder cancer cell lines in vitro, and it was more cytopathic than AxE1AdB or dl922-947 in the cancer cell lines. AxdAdB-3 was not cytotoxic against HCV29. Direct instillation of AxdAdB-3 into the bladder of the orthotopic model inhibited tumor growth, leading to significantly prolonged survival. Conclusions: Oncolytic viral therapy delivered by instillation of AxdAdB-3 is a promising tool for treating bladder cancer.