A NOVEL VACCINIA VIRUS BACKBONE FOR THE DELIVERY OF IMMUNOTHERAPEUTIC GENES

摘要

Vaccinia virus has a large and still incompletely understood genome although several strains of this virus are already in clinical development for the treatment of cancer. For the most part, clinical candidates have been attenuated from their wild type vaccine strains through deletion of metabolic genes like the viral thymidine kinase gene. We decided to carry out a more in depth understanding of the genetic elements of vaccinia which could be modulated to improve the oncolytic/therapeutic characteristics of the virus. Using a variety of cancer cell lines and primary tumor explants, we performed a fitness assay that compares head to head five wild-type Vaccinia strains to identify the genetic elements that together create an optimal 'oncolytic engine'. Using a transposon insertion strategy and deep sequencing of viral populations we systematically examined vaccinia genes that do or do not play a role in the therapeutic activity of the virus. Our studies allowed us to identify large areas of the vaccinia genome that when deleted, augment the oncolytic activity of a newly created recombinant virus (35 genes deleted). This novel virus was compared to five vaccinia strains currently in the clinic and in a variety of assays, the deleted virus displayed superior therapeutic activity and an enhanced safety profile. Studies in a variety of in vitro and in vivo models will be presented illustrating the strategy we have used to create this optimized oncolytic virus platform. We are currently carrying out further pre-clinical studies to accelerate the translation of this new virus into the clinic.