) This application is the competitive renewal of a P01 whose goal was to develop and evaluate approaches for gene therapy in the treatment of localized malignancies, using malignant mesothelioma as the paradigm. The rationale for this proposal came from studies showing that tumor cells transduced with an adenoviral vector containing the Herpes Simplex thymidine kinase (HSVtk) gene were killed after exposure to the normally non-toxic anti-viral drug ganciclovir (GCV) and that a powerful """"""""bystander effect"""""""" existed. Accordingly, a phase I Clinical Trial was conducted in 26 patients with mesothelioma using an Ad. HSVtk virus. Intrapleural administration of Ad. HSVtk was safe and resulted in consistent, dose-related, gene transfer that was detectable by immunohistochemical analysis. The goals of this new P01 are to continue these studies by conducting additional clinical and scientific studies aimed at maximizing the effectiveness of the gene transfer achieved, to evaluate approaches to augment gene transfer, and to develop non-invasive techniques to monitor gene transfer. The long term goal is to move to phase II trials. Each of three highly interactive Projects, will focus on this goal. In the Mesothelioma Clinical Trials project, new phase I clinical trials are proposed that are designed to test hypotheses related to use of a new E1/E4-deleted vector, administration of vector in an adjuvant setting, and administration of increased doses of GCV. This project will also evaluate non-invasive gene transfer imaging developed and test the most promising new therapeutic approach developed in Project 2. The Pharmacokinetics and Imaging project will focus on ways to optimize the delivery of ganciclovir and on the development and use of a radioactively-labeled GCV analog that can be used as a tool to allow non-invasive assessment of gene transfer using positron emission tomography. The Vector Development & Preclinical Studies project will develop new scientific approaches to augment the efficacy of the HSVtk that is introduced into the tumor cells and/or to increase the amount of gene transfer. This will be accomplished by developing improved suicide genes, replicating adenoviral vectors, and augmentation of anti-tumor immune responses. These projects will be supported by four cores: Administrative, Pathology, Translational Services, and Biostatistics/Data Management.
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