Phase I Trial of Adenoviral Mediated Suicide Gene Therapy with HSV-tk followed by Intraveneous Administration of Ganciclovir in Patients with Locally Advanced and Refractory Superficial Bladder Cancer

Erwin Schrödinger Fellowship J 1875 Gene Therapy of Uro-oncologic diseases Shahrokh SHARIAT 08.05.2000 -Bladder Cancer: + Phase I trial of adenoviral mediated suicide gene therapy with HSV-tk followed by intravenous administration of gancic lovirin patients with locally advanced and refractory superficial bladder cancer +Pre- clinical Studies of bladder cancer gene therapy: Compare the safety and cell killing efficacy of ganciclovir, acyclovir, penciclovir and valacyclovir following ADV-tk transduction; Test the hypothesis that multiple administrations of.. HSV-tk vector can trigger superior cell killing efficacy compared to the conventional single dose injection, without increasing the toxicity; Test the hypothesis that combinations. of HSV-tk/nucleoside with retinoids will augment tumor growth suppression and animal. survival compared with either treatment alone mainly through increased bystander effect; Test the hypothesis that combinations of FSV-tk/nucleoside analogue with standard and investigational chemotherapeutic agents will enhance the cell killing efficacy through synergistic activity. -Prostate Cancer: In addition to the prostate cancer with confirmed metastatic disease, up to-30% of patients thought to have clinically localized prostate cancer fail surgery and irradiationtherapy because of early dissemination of vicrometastatic disease. The abscence of curative therapies warrants the need for novel strategies such as gene therapy. We will attempt to develop an anti-tumor vaccine that boosts the immune response to prostate cancer. Specifically, we will test which cells killed (primarily either by apoptosis or by necrosis) and then introduced into the host (either by intravenous (iv) or subcutaneous (sc) routes) are more immunogenic. We will trigger apoptosis in the vaccinating cells by gamma-irradiation or caspas-based methods such as tranaduction with ADV-FKBP/ICE and overnight incubation withdimerizing drug. Necrosis will be triggered by heat schock/freeze- thaw or simulated by disruption (homogenization). We will also use cells killed by HSV-tk + ganciclovir, which cause apoptotic and necrotic cell death. To enhance immunogenicity, cells will be pre-infected with AdBP1, coexpressing F17-1 and IL-12. We will first determine whether apoptotic or necrotic prostatetumor cells are more efficacious vaccine against a secondary tumor challenge through evaluation of the resistance to the challenge (tumor measurement) as well as CTL assays on splenoytes of treated and control animals.