Recombinant aoenoviral-mediatedintrapleural gene therapy for maugnant mesotheljoma: Preliminary findings of a phase I clinical trial

Malignant mesothelioma (MM) is a neoplasm with a dismal prognosis for which no effective therapy currently exists. We have initiated a Phase I clinical trial to assess the safety and feasibility of treating patients with MM by intrapleural delivery of a recombinant adenovirus (rAd) containing the Herpes Simplex Virus thymidine kinase gene (HSVtft), driven by the Rous Sarcoma Virus (RSV) promoter, Into the pleural space, followed by systemic treatment with the antiviral drug ganciclovir (GCV). Prior implementation of the rAd.RSVrWGCV protocol in animal models of mesothelioma resulted in significant reduction of tumor burden and prolongation of survival with minimal systemic toxicity. Our clinical trial is a dose escalation study of 12 patients evaluating the maximallytolerated intrapleural dose of rAd.RSVWc, delivered at four dose levels In logarithmic increments. Three patients have completed treatment at the initial dose level of 1x10? plaque forming units (pfu) of Ad.RSVWt with minimal complications. Minor toxicitles seen included low-grade fever after viral Instillation, mild-moderate anemia, and transient elevation of liver function tests. One patient had evidence of gene transfer on post-viral biopsy samples via immunohistochemical analysis utilizing a polyclonal rabbit anti-HSVtfc antibody. Electron microscopy of two patients' post-viral biopsy samples revealed intranuclear adenovirus-like structures. Patient lymphocytes, sera, pleural fluid, and tumor tissue samples were obtained at several time points throughout the study for evaluation of the host's immune réponses to the native MM, tk transgene, and rAd vector.