Preclinical Studies

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This proposal is the continuation of an ongoing project to generate the targeted preclinical data needed to design and improve our current and future clinical trials in mesothelioma. Although the aims are hypothesisdriven and include mechanistic studies, this project will continue to be "translational" in nature. The current focus is on immunotherapy. Over the past threee years, the major hypothesis of this project has been that the success of immunotherapy can be improved by augmenting the ability of effector cells to successfully traffic into tumors and/or by preventing the inactivation of immune cells that do enter the tumors. This concept has been tested and validated in mesothelioma models using combinations of immuno-gene therapy with surgical debulking and with cyclooxygenase-2 (COX-2) inhibition. These ideas are being incorporated in the planned Phase 2 trials. In this proposal, well-characterized pre-clinical mouse models will be used to develop practical approaches that can be used to augment efficacy in immuno- and immuno-gene therapeutic trials. In Specific Aim 1, the optimal approaches and mechanisms of combining blockade of tumor-induced immunosuppresion (by inhibiting TGF-beta and COX-2) with immuno-gene and adoptive transfer therapy will be explored. The goal of Specific Aim 2 is to study the optimal approaches and mechanisms of combining gemcitabine chemotherapy with immuno-gene and adoptive transfer therapy. Specific Aim 3 will explore the optimal approaches and mechanisms of increasing the trafficking of immunocytes to tumors after immunogene and adoptive transfer therapy using agents targetting the tumor vasculature (DMXAA). Specific Aim 4 will evaluate and improve trafficking of human anti-mesothelin T-bodies. At the suggestion of the reviewers, Specific Aim 5 was added to conduct experiments using patient material to assess the effects of immunotherapy and immunotherapy augmentation. Future studies will explore additional immuno- and immuno-gene therapy opportunities or augmenting immune therapies. Effective approaches will be implemented into future clinical trials conducted by the other investigators in this PO1. This project will thus continue to be the critical "testing ground" to allow approaches to move from "bench to bedside".