Adenoviral-Mediated Herpes Simplex Virus Thymidine Kinase-Gansislovir Gene Therapy for Malignant Pleural Mesothelioma: Results of Phase 1 Clinical Trial.
DH Sterman, SM Albelda, LE Coonrod, KM Amin, K Molnar-Kimber, JM Wilson, LA Litzky, LR Kaiser and J Treat. Thoracic Oncology Research Laboratory, University of Pennsylvania Medical Center, Philadelphia, PA, USA.
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-GCV. Fifteen patients have completed treatment at dose levels up to 3.2x10(11) 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 cruptions near the instillation site. One patient developed asymptomatic alvcolar infiltrates in the contralateral lung after vector delivery.
Evaluation of selected post-gene delivery biopsy samples revealed evidence of tk gene transfer via DNA PCR and in situ hybridization in a dos-dependent fashion. Neutrophil-predominant inflammatory responses were seen on IHC analysis of post-vector administration biopsy samples.
In summary, Ad.RSVtk/GCV gene therapy is safe in MM patients, and there appears to be evidence of tk gene transfer in a dose-dependent fashion.