Malignant gliomas represent the single most costly and morbid neoplasm per capita. During previously funded years,this Program Project has evaluated a pipeline of potential biologic therapies of this tumor. We now propose to manufacture and translate one therapy, an oncolytic HSV-1 vector (""""""""MGH-2""""""""), which activates prodrugs, into three clinical phase I trials. At the same time this project proposes to continue to develop additional tumor-targetting therapies, novel imaging tools and to understand mechanisms of potential resistance. Four projects and three Cores are united in collaboration with GMP-production facilities of Dr. Glorioso, as a resource for the brain-tumor consortium (NABTT) to explore gene therapy for glioblastomas. Project 1 (Chiocca) will determine mechanisms of the host response to the oncolytic virus and how this host response can be modulated to provide more efficient tumor killing . Project 4 (Breakefield/Sena-Esteves) will enhance tumor targeting by HSV-1 vectors specifically directed against mutant EGFr in combination with Neural Precursor cells to protect normal brain from tumor recurrence. Project 2 (Carter) will develop a complementary cellular therapeutic strategy to target human T lymphocytes to intracranial glioblastomas by genetically engineering them to express chimeric immune receptors which recognize antigens identified in Projects I and 3. Project 3 (Weissleder ) will identify peptides which selectively label and image therapeutic NPC and T cells and oncolytic viruses in glial tumors, and correlate novel imaging modalities with the biologic therapies explored in Projects 1,2 and 4.Clinical Core B (Hochberg/Glorioso/Tufaro) will pilot the production of MGH-2 and create sufficient GMP product to perform the three phase I trials. The Core will generate the FNDs and trial protocols as well as toxicity and human efficacy endpoints in support of all trials at both the MGH and OSU institutions. The vector will be offered to CTEP for phase II NABTT trials. . Human and rodent and pre-clinical marmoset studies will be supported by statistical oversight (Dr. Finkelstein) and histologic, molecular pathologic and immunocytochemical evalutions of brain tumor tissue (Core C, Louis). This program defines rational and scientific means to evaluate and expand the potential of gene therapy for brain tumors.
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