The overall goal of this PO1 is to develop and evaluate approaches for gene therapy in the treatment of localized malignancies using malignant mesothelioma as the paradigm. Mesothelioma is an excellent candidate for the development of gene therapy because the disease is uniformly lethal with no effective therapies available, morbidity and mortality are the result of regional intrathoracic disease, and the tumor is localized to an anatomically defined space to which there is easy access. The rationale for this proposal comes from studies showing that tumor cells transduced with an adenoviral vector containing the Herpes Simplex thymidine kinase (HSVtk) gene are killed after exposure to the normally non-toxic anti-viral drug ganciclovir (GCV) and that a powerful """"""""bystander effect"""""""" exists (i.e. uniform killing occurs even when only a small percentage of cells are transduced). Studies were extended to an animal model of human mesothelioma in which established mesothelioma tumors growing within the peritoneal cavity of immunodeficient mice were eradicated by intraperitoneal administration of the adeno-HSVtk vector followed by treatment with GCV. The grant consists of three projects and four cores. The goals of Project I are to develop new vectors based on adenovirus and adeno-associated virus expressing the HSVtk gene and to test these vectors for persistence and the development of immune response in animal models of mesothelioma. The goals of Project 2 are to test and optimize the """"""""first generation"""""""" vector and the new vectors developed in Project 1 with regard to efficacy in the treatment of mesothelioma in animal models. The second focus of this project will be to study the mechanisms responsible for the efficacy of the HSVtk/GCV system in eradicating tumors. The goals of Project 3 are to use the vectors developed in Projects 1 and 2 to treat patients with malignant mesothelioma and to obtain information about the biologic effects of adenoviral vectors in the treatment of localized malignancy. A Phase I clinical trial is proposed using the first generation virus that will define the potential systemic, intrathoracic, and immunologic toxicities and determine a maximally tolerated dose. An important feature of this trial is a videothoracoscopic biopsy of pleural tumor after instillation of virus that will allow evaluation of gene transduction. These findings will form the basis of a Phase II clinical trial designed to evaluate possible efficacy. Using this information, the safety and efficacy of new viral vectors developed in Projects 1 and 2 will be tested in additional Phase I and II trials. The cores that support these projects include an Administrative Core, the Human Applications Laboratory (to make clinical grade viral vectors), a Cellular Morphology Core, and an Animal modeling and Toxicology Core.
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