This proposal is the continuation of an ongoing project to generate the targeted preclinical data needed todesign and improve our current and future clinical trials in mesothelioma. Although the aims are hypothesisdrivenand include mechanistic studies, this project will continue to be 'translational' in nature. The currentfocus is on immunotherapy. Over the past threee years, the major hypothesis of this project has been thatthe success of immunotherapy can be improved by augmenting the ability of effector cells to successfullytraffic into tumors and/or by preventing the inactivation of immune cells that do enter the tumors. Thisconcept has been tested and validated in mesothelioma models using combinations of immuno-gene therapywith surgical debulking and with cyclooxygenase-2 (COX-2) inhibition. These ideas are being incorporatedin the planned Phase 2 trials. In this proposal, well-characterized pre-clinical mousemodels will be used to developpractical 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-inducedimmunosuppresion (by inhibiting TGF-beta and COX-2) with immuno-gene and adoptive transfer therapy willbe explored. The goal of Specific Aim 2 is to study the optimal approaches and mechanisms of combininggemcitabine chemotherapy with immuno-gene and adoptive transfer therapy.
Specific Aim 3 will explore theoptimal approaches and mechanisms of increasing the trafficking of immunocytes to tumors after immunogeneand 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 thesuggestion 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 willexplore 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 thisPO1. This project will thus continue to be the critical 'testing ground' to allow approaches to move from'bench to bedside'.
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