Brain Tumor Therapy with Replication-Competent Virus Vectors Expressing Secretory Fusion Proteins

Replication-Competent herpes simplex virus (HSV) vectors are attractive means for brain tumor therapy, because they can replicate selectively in a tumor and spread, exhibiting oncolytic activity, yet cause no harm in the normal brain tissue. Furthermore, they enable amplified gene delivery within a tumor. We have performed a phase I clinical trial using double-mutated HSV (G207) in malignant glioma patients, which roved the safety of the virus at the highest obtainable dose. To advance this promising approach, we propose to develop novel and efficacious therapies by combining the oncolytic virus activity with the delivery of genes encoding secretory fusion proteins. G47Delta, a new oncolytic virus created from G207, will be used to generate two new types of HSV vectors. G47Delta has an additional mutation that confers a high replication capacity, prevents down-regulation of MHC class I proteins expression in host cells, and allows to retain safety features. In the first approach, p53 will be fused with the HSV-1 tegument protein VP22 that confers a capability to spread by diffusion and accumulate in the nuclei of neighboring cells while retaining the proapoptotic p53 functions. In the second approach, the extracellular domain of B7-1, a potent T lymphocyte costimulatory molecule, ill be fused to IgG(Fc), so that the dimeric protein is secreted and manifests strong stimulation for specific antitumor immunity. For in vivo evaluation, we will utilize mouse syngeneic brain tumor models as well as transgenic mice that develop spontaneous brain tumors.