The treatment of malignant mesothelioma (MPM) remains inadequate. New therapies, such as gene therapyor immuno-gene therapy, are desperately needed. This Project is based on a previous series of Phase Iclinical trials using recombinant, replication-deficient adenoviral (Ad) vectors containing the Herpes SimplexThymidine Kinase (HSVtk) gene in 34 MPM patients. Significant intratumoral HSVtk gene transfer wasachieved and some radiographic and clinical responses were noted, including 2 patients who had durablecomplete responses in delayed fashion, highly suggestive of anti-tumor immune responses. On this basis,the focus of laboratory and clinical work was shifted to genetic immunotherapy of thoracic malignancies.Based on strong preclinical data, a new Phase I clinical trial using a single dose of intrapleural adenoviralinterferon beta (Ad.lFN-beta) for patients with MPM and malignant pleural effusions (MPE) was conducted.The approach was safe and a number of immunologic responses, as well as clinical responses wereobserved. The goal of this Project is to continue and extend these clinical trials aimed at patients withmesothelioma. In the first aim, a Phase 1 trial will be conducted to assess the safety, toxicity profile, immuneresponses, and clinical effect of two intrapleural doses of Ad.lFN-beta for patients with MPE/MPM.
SpecificAims 2 and 3 will consist of Phase 2 clinical trials testing approaches in patients with MPM that weredeveloped from our preclinical studies to augment efficacy.
Aim 2 will determine the efficacy and immuneresponses associated with the delivery of two doses of Ad.lFN-beta as neo-adjuvant therapy in combinationwith surgical debulking and adjuvant COX-2 inhibitors in patients with MPM.
Aim 3 will determine theefficacy and immune responses associated with the delivery of two doses of Ad.lFN-beta in combination withchemotherapy and adjuvant COX-2 inhibitors in patients with MPM.
In Aim 4, investigators will begin thesteps needed to develop an adoptive immunotherapy trial using genetically engineering T-lymphocytesreactive against mesothelin for patients with mesothelioma and other tumors expressing this tumor antigenafter preclinical optimization.
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