) The short term goals of this project are to develop new strategies to augment HSVtk therapy and to test these new systems in well characterized animal models of mesothelioma. The long term goals are to move the most promising of these new approaches into phase I clinical trials for mesothelioma. The first specific aim will be to develop and evaluate adenoviruses containing """"""""improved"""""""" versions of HSV/k. Two hypotheses will be tested: (1) mutant versions of HSVtk with increased affinity and/or improved kinetics will augment tumor killing efficacy and (2) a chimeric HSVtk/VP22 fusion protein will augment tumor killing efficacy due to the ability of the VP22 protein (a tegument protein produced by Herpes Simplex Virus) to transfer from transduced to non-transduced cells. Accordingly, Ad vectors containing mutant HSVtk's with augmented ability to phosphorylate ganciclovir and containing a chimeric transgene consisting of HSVtk coupled to the HSV-VP22 protein will be produced and tested. The second specific aim will be to develop and evaluate replication-competent adenoviral vectors expressing HSVtk. Two hypotheses will be tested: (1) use of replicating vectors (even if only 1 or 2 rounds of replication occur) will be able to deliver transgene to a larger number of tumor cells and thus enhance efficacy and (2 ) adenoviral vectors in which a tumor-associated promoter regulates EIA expression will confer replication selectivity in the appropriate tumor cells. A fully replicative virus containing the HSVtk gene inserted into the E3 region will be produced and studied. In addition, Ad mutants that replicate selectively in tumors will be constructed and tested. This will be accomplished by disrupting the normal Ad EIA promoter region and inserting tumor-selective promoters into this region. The third Specific Aim will be to evaluate the use of specific cytokines to augment HSVtk/GCV efficacy. The hypothesis that immune augmentation can increase the efficacy of HSVt/dGCV gene therapy will be tested. Intracavitary Ad. HSVtk therapy will be combined with intracavitary injection of specific cytokines that are commercially available and have been shown to have some efficacy in mesothelioma (IL-2, Interferon-cq and interferon-7). In addition, investigators from this Project will work closely with investigators from this Project to provide the animals models needed for their pharmacokinetic and imaging studies.
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