The overall hypothesis of this project is that immuno-gene therapy can be used successfully to treat malignant pleural mesothelioma (MPM). The Project will continue to move the preclinical findings from Projects 2 and 3 into cutting-edge clinical trials (bench-to-bedside);and to provide clinical data and specimens back to Projects 2 and 3 to inform improvements in the next iteration of clinical trials (bedside-to bench). The first focus of this project is to continue and extend successful trials using intrapleural injections of an adenovirus (Ad) expressing type 1 interferon (Ad.lFN). Based on preclinical data from Project 2, a Phase 1/2 trial was initiated combining two Ad.IFN-alpha doses (given 3 days apart) with concomitant Celecoxib administration, followed two weeks later by 4-6 cycles of either front-line (pemetrexed/cisplatin/) or second-line (gemcitabine/carboplatin) chemotherapy.
Aim 1 of this proposal is to complete the Phase 2 trial to determine if the response rate warrants moving this therapy to a larger randomized Phase 2 or 3 trial by either industry or cooperative groups. The second focus of the Project is adoptive T cell therapy using T cells with chimeric antigen receptors (CARs) initially targeted to the mesothelioma tumor surface antigen, mesothelin. Given potential safety concerns with some other CARs, a trial using T-cells transduced with GMP grade mRNA will be conducted (Aim 2A). Since CAR expression time is limited, if any
Malignant mesothelioma is currently considered incurable. New approaches are needed. This project will continue to conduct a series of novel clinical trials using an adenovirus making an inflammatory cytokine (inteferon-alpha) or by transfusing patient with lymphocytes that have been genetically altered to kill tumor cells.
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