Strategies to Improve Adenovirus and Reovirus Vectors for Oncolytic Virotherapy

Abstract The research described in this thesis focused on generating more effective adenovirus and reovirus vectors and to obtain more reliable parameters of anticancer efficacy. Four different approaches were studied 1) Modification of capsid proteins to alter the tropism of the wild-type virus; 2) Forward-genetic strategies were used to obtain more potent viruses; 3) The modified viruses, obtained with the help of forward genetics, have been analyzed and compared with wild-type viruses on primary cultures and stem-like cultures; 4) Mesenchymal stromal cells (MSC) were evaluated as carrier cells for reovirus delivery to cancer cells. Adenovirus does not have a natural preference for transformed cells. Modifications endowing the oncolytic preference are widely study. In chapter 4 the effect of the removal of adenovirus capsid protein IX was studied. Next to a virus vector with an altered cell tropism fundamental knowledge about protein IX was gained. In chapter 5 it was shown that truncation of the i-leader open-reading-frame en

Surface chemistry-dependent antiviral activity of silver nanoparticles

Environmental Biolog

Replicating reoviruses with a transgene replacing the codons for the head domain of the viral spike

Therapeutic cell differentiatio

Isolation of Reovirus T3D Mutants Capable of Infecting Human Tumor Cells Independent of Junction Adhesion Molecule-A

Gene regulation and cell differentiatio

Mammalian orthoreovirus T3D infects U-118 MG cell spheroids independent of junction adhesion molecule-A

Microscopic imaging and technolog

Heterogeneous reovirus susceptibility in human glioblastoma stem-like cell cultures

Gene regulation and cell differentiationTherapeutic cell differentiatio

Locally-Delivered T-Cell-Derived Cellular Vehicles Efficiently Track and Deliver Adenovirus Delta24-RGD to Infiltrating Glioma

Therapeutic cell differentiatio

A cathepsin-cleavage site between the adenovirus capsid protein IX and a tumor-targeting ligand improves targeted transduction

Gene regulation and cell differentiatio

Enhanced transduction of CAR-negative cells by protein IX-gene deleted adenovirus 5 vectors

In human adenoviruses (HAdV), 240 copies of the 14.3-kDa minor capsid protein IX stabilize the capsid. Three N-terminal domains of protein IX form triskelions between hexon capsomers. The C-terminal domains of four protein IX monomers associate near the facet periphery. The precise biological role of protein IX remains enigmatic. Here we show that deletion of the protein IX gene from a HAdV-5 vector enhanced the reporter gene delivery 5 to 25-fold, specifically to Coxsackie and Adenovirus Receptor (CAR)-negative cell lines. Deletion of the protein IX gene also resulted in enhanced activation of peripheral blood mononuclear cells. The mechanism for the enhanced transduction is obscure. No differences in fiber loading, integrin-dependency of transduction, or factor-X binding could be established between protein IX-containing and protein IX-deficient particles. Our data suggest that protein IX can affect the cell tropism of HAdV-5, and may function to dampen the innate immune responses against HAdV particles. (C) 2010 Elsevier Inc. All rights reserved.Transplantation and immunomodulatio