Improvement of oncolytic adenovirus vectors through genetic capsid modifications

Abstract

Recombinant viral vectors hold great promise in the field of cancer gene therapy. While a plethora of viruses is being evaluated as oncolytic agents, human adenoviruses of serotype 5 (HAdV-5) are among the most popular of viruses to be developed. Although clinical studies have demonstrated safety of cancer gene therapy with HAdV-5-derived vectors, the efficacy still needs further enhancement. Several factors have been identified that limit the anti-tumor efficacy. One major bottleneck is the inadequate penetration and spread of the virus within the tumor. This is attributable, at least in part, to the low or heterogeneous expression of the coxsackie and adenovirus receptor (CAR) on the tumor cells. This thesis describes the development and preclinical evaluation of novel tumor-targeted HAdV-5 vectors, through implementing the genetic fusion of capsid proteins (protein IX and fiber) with a variety of tumor-targetin g polypeptides.