Treatment of Pleural Mesothelioma in an Immunocompetent Rat Model Utilizing Adenoviral Transfer of the Herpes Simplex Virus Thymidine Kinase Gene

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Abstract
Previously, we have treated malignant mesothelioma (MM) growing in the peritoneal cavity of immunodeficient mice utilizing a recombinant adenovirus vector carrying the herpes simplex virus-thymidine kinase gene (Ad.RSVtk) followed by administration of the anti-viral drug ganciclovir (GCV). To mimic more closely the clinical situation in human MM, a syngeneic model of pleural MM was developed in immunocompetent Fischer rats. Administration of Ad.RSVtk into the pleural space of animals with established multifocal tumor followed by systemic GCV therapy resulted in significant tumor regression at 20 days in HSVtk/GCV-treated animals (average tumor weight 0.6 ± 0.2 gram; n = 12) versus control animals (average weight 5.4 ± 0.2 grams; n = 21; p < 0.001). In additional studies, Ad.RSVtk/GCV-treated animals had a mean survival of 34 days (average tumor weight 1.0 ± 0.3 gram at death) versus 26 days in control animals (average tumor weight 6.2 ± 0.6 grams at death). A significant reduction in tumor burden was also seen when more advanced, bulkier disease was treated. These studies demonstrate the Ad.RSVtk/GCV system is effective in the treatment of pleural-based tumors in an immunocompetent host. However, there are limitations to this treatment approach that result in only small increments in survival. In vivo transfer of the herpes simplex virus-thymidine kinase gene (HSVtk) followed by the anti-viral drug ganciclovir (GCV) has previously been shown to be an effective antitumor therapy in immunodeficient animal models with the use of an adenovirus vector. However, recent studies with adenoviral vectors show that immune responses limit the efficacy and persistence of gene expression. The aim of this study was to evaluate the efficacy of the Ad.RSVtk/GCV system in an immunocompetent host. Utilizing a syngeneic model of pleural malignant mesothelioma (MM) in Fischer rats, administration of Ad.RSVtk into the pleural space of animals with established multifocal tumor followed by intraperitoneal GCV therapy resulted in a significant reduction of tumor burden. These studies demonstrate the HSVtk/GCV system is efficacious for the treatment of pleural-based malignant mesothelioma in an immunocompetent host with the use of an adenovirus vector.