Our objective is to develop and refine a molecular-based strategy for the treatment of malignant gliomas using genetically engineered HSV. In order to meet this objective and identify a human HSV therapeutic, we will undertake extensive biologic characterization of each genetically engineered HSV produced in the first Project. We will produce, titer and maintain reference stocks of each of these constructs and will conduct primary screening of each (replication competence, gene expression, cytopathic effect, neurovirulence) to determine suitability for in vivo efficacy testing. Viruses that prove to be acceptable will be provided to investigators in the third Project and both groups will define the anti- tumor effects of genetically engineered HSV in vivo using an intracerebral glioma-scid mouse model and in a flank tumor-nude mouse model. Further, we will assess escape mechanisms by which tumor cells survive destruction of genetically engineered HSV constructs in an effort to improve virus delivery and efficacy as an oncolytic agent. We will also evaluate the host immune response to HSV treatment of intracranial gliomas as it develops both locally (in the tumor) and systemically using the C57BL/6 mouse as a host for the syngeneic Gl-261 malignant glioma. For engineered HSV in which cytokine genes have been inserted, their ability to suppress immune responsiveness to HSV or enhance anti-tumor immune responses will be sought. Finally, for those selected HSV that offer excellent anti-tumor effects with minimal injury to normal brain, we will conduct and evaluate their potential safety for use in human clinical trials by intracerebral testing in a very sensitive simian primate, Aotus trivirgatus.
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