GENE THERAPY OF MALIGNANT MESOTHELIOMA USING E1 DELETED ADENOVIRUS

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Malignant mesothelioma (MM) is a neoplasm for which no effective therapy currently exists. We conducted a Phase I clinical trial to assess the safety and feasibility of intrapleural delivery of recombinant adenovirus (rAd) containing the Herpes Simplex Virus thymidine kinase gene (HSVtk) driven by the Rous Sarcoma Virus (RSV) promoter into the pleural space of patients with MM followed by systemic treatment with the antiviral drug ganciclovir (GCV) for 14 days. Prior implementation of the rAd.RSVtk -GCV protocol in animal models of MM resulted in significant reduction of tumor burden and prolongation of survival with minimal systemic toxicity. The clinical trial was a dose escalation study designed to determine the maximally-tolerated intrapleural dose of rAd.RSVtk. Twenty-six patients have completed treatment at dose levels up to l.0x10 12 plaque forming units (pfu) Ad.RSVtk with minimal complications. Toxicities seen include low-grade fever after viral instillation, anemia, transient elevation of liver function tests, and vesicular skin eruptions near the instillation site. Evaluation of selected post-gene delivery biopsy samples revealed eavidence of tk gene transfer via DNA PCR, in situ hybridization, and immunohistochemistry in a dose-dependent fashion. Neutrophil-predominant inflammatory responses were seen on IHC analysis of post-vector administration biopsy samples. Patients develop significant evidence of humoral and cellular immune responses against the adenoviral vector. In summary, Ad.RSVtk/GCV gene therapy is safe in MM paatients, there appears to be evidence of TK gene transfer in a dose-dependent fashion, and recombinant adenoviruses elicit strong immune responses when delivered into the pleural space.