648. Transductionally Modified Oncolytic Adenoviruses for Treatment of Advanced Pancreatic Cancer

Abstract

Top of pageAbstract 216 367 new cases of pancreatic cancer are estimated worldwide, with 213 462 subsequent deaths and the incidence is increasing. A reason for the strikingly low survival is the fact that clinical symptoms appear late and the lack of good therapy modalities. Virotherapy with conditionally replicating adenoviruses (CRADs) has been explored for enhanced tumor transduction and amplification of effect. Expression of the coxsackie adenovirus receptor (CAR) has been shown to be expressed variably in many cancer types thus compromising adenoviral transduction. We evaluated infectivity enhancement approaches for pancreatic cancer in vitro using a selection of cell lines (HPAC, Capan-2, HS766T,SW1990, Panc-1) and clinical samples fresh from patients. Capsid modifications utilized were RGD-4C, serotype chimerism (5/3), and polylysine modification of the adenoviral fiber. The RGD- 4C motif in the fiber knob allows adenovirus binding to integrins, serotype chimerism targets the Ad3 receptor and polylysine modification allows binding to heparin sulphate proteoglycans, thus circumventing potentially lacking or variable expression of CAR. To measure transduction efficacy, cell lines and clinical samples were infected with replication deficient viruses expressing firefly luciferase or b-galactosidase. After 24 hours of infection, cells were lysed and relative light units were measured and compared to wild type capsid containing viruses. The oncolytic effect of CRADs with similiar capsid modifications was tested by measuring mitochondrial activity of the cell lines post infection. Our data showed the benefits of infectivity enhancement for pancreatic cancer. In all cell lines and clinical samples either the pk7 or 5/3 capsid modified viruses showed significantly better transduction efficacy over wild type. Also CRADs with chimeric or polylysine modifications showed superior in vitro oncolytic potency compared to wild type. For in vivo analysis, we utilized a subcutaneous model of pancreatic cancer and comparison of capsid modified CRADs is ongoing. More importantly, we have developed orthotopic models of disseminated pancreatic cancer for comparing candidate CRADs and data will be presented at the meeting.