ET-29 * AN OPTIMIZED ONCOLYTIC ADENOVIRUS FOR GLIOMA THERAPY: SPECIFIC TARGETING, EFFICIENT INFECTION, AND RESTRICTED REPLICATION IN GLIOMA

Abstract

The dismal clinical context of advanced-grade glioma calls for the development of novel strategies with the potential for direct patient impact. For this, conditionally replicating adenoviruses (CRAds) represent a potentially effective approach for glioma therapy. In order to maximize the efficiency and safety of CRAds, several modifications may be instituted, including specific and efficient targeting, as well as tumor-restricted replication. A glioma-specific targeted fiber, which dictates the attachment of an adenoviral vector to a target cell, was developed and generated specific cell-targeting fibers through the incorporation of glioma- specific phage-panned peptides on a Fiber Fibritin-based Ad5 fiber, designated as ‘MGFF’. We then generated Ad5MGFF-CMV-GFP (and Survivin-E1) through a homologous recombination with pVK900. Replication-incompetent Ad5MGFF-CMV-GFP was used with 300MOI (vp/cell) to investigate glioma-specific infectivity. Conditionally replicating Ad5MGFF-SurE1 was used to test the specific oncolytic activity on Glioma. The fiber-modified Ad5MGFF shows structural stability and stable viral growth kinetics, indicating that the performed modification had no effect on viral particle formation. This glioma-specific Ad5MGFF-CMVGFP had a mean 68% infection rate in glioma cell lines while showing less than 1% infection in normal (non-neoplastic) cell lines (including normal human astrocytes) as well as other cancer cell lines. Conditionally replicating Ad5MGFF-SurE1 shows highly specific oncolytic activity on glioma cell lines. In this study, we have generated a novel glioma specific adenoviral vector (Ad5MGFF). The infection and oncolytic activity of this virus was almost exclusive in specificity to glioma. The change of tumor growth and the survival effects on glioma-bearing mice will follow.