Advanced Oncolytic Adenovirus Enabling Systemic Therapy of PDAC

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and refractory malignancy, whose five-year survival rate remains only 9%. Less than 20% of the patients visiting clinics are candidates for surgery because most PDAC patients have advanced diseases at the time of diagnosis. The majority of PDAC patients therefore require systemic therapies. While there is promising advance in cancer therapeutics, their median survival is < 6 months. These PDAC patients need development of new approaches for systemic treatment. Oncolytic viruses are promising anti-cancer agents under development. Among them, oncolytic adenovirus (OAd) is one of the strong candidates. Despite needs of systemic treatments for PDAC, the vast majority of OAds are designed for local administration due to several obstacles, such as sequestration to normal organs, difficulty for selective delivery to the tumor, neutralizing antibodies, and hemagglutination. Aiming at development of an OAd enabling treatment of advanced PDAC patients by systemic injection, we will tackle these obstacles in this project. Adenoviruses have more than 50 serologically defined types, and this is a unique feature enabling escape from neutralizing Abs. However, simple switching the backbone has not realized cancer specificity because tropisms of adenoviruses are not cancer specific. We previously identified mesothelin (MSLN)-targeted OAd for PDAC treatment and reported the feasibility of knob switch. We will generate a new series of OAds based on a variety of Ad species other than Ad5, where the fiber-knob regions are replaced by the knob with pancreatic cancer-specific binding motif in the original binding domain (AB-loop). We hypothesize that these viruses will allow selective delivery to the tumor by systemic injection while avoiding the effect of nAbs and hemagglutination. This project is expected to overcome the current and potential issues of systemic therapy of PDAC with oncolytic virus by exploiting the advantages of the adenoviral vector system and our unique advantages in adenovirus targeting strategies. The potential impact of systemically injectable OAd for PDAC is significant.