title: Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma.
abstract: Malignant pleural mesothelioma is a fatal neoplasm that is unresponsive to standard modalities of cancer therapy. We conducted a phase I dose-escalation clinical trial of adenoviral (Ad)-mediated intrapleural herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) gene therapy in patients with mesothelioma as a model for treatment of a localized malignancy. The goals of this phase I trial were to assess the safety, toxicity, and maximally tolerated dose of intrapleural Ad.HSVtk, to examine patient inflammatory response to the viral vector, and to evaluate the efficiency of intratumoral gene transfer. Twenty-one previously untreated patients were enrolled in this single-arm, dose-escalation study with viral doses ranging from 1 x 10(9) plaque-forming units (pfu) to 1 x 10(12) pfu. A replication-incompetent recombinant adenoviral vector containing the HSVtk gene under control of the Rous sarcoma virus (RSV) promoter-enhancer was introduced into the pleural cavity of patients with malignant mesothelioma followed by 2 weeks of systemic therapy with GCV at a dose of 5 mg/kg twice a day. The initial 15 patients underwent thoracoscopic pleural biopsy prior to, and 3 days after, vector delivery. The last six patients underwent only the post-vector instillation biopsy. Dose-limiting toxicity was not reached. Side effects were minimal and included fever, anemia, transient liver enzyme elevations, and bullous skin eruptions, as well as a temporary systemic inflammatory response in those receiving the highest dose. Strong intrapleural and intratumoral immune responses were generated. Using RNA PCR, in situ hybridization, immunohistochemistry, and immunoblotting, HSVtk gene transfer was documented in 11 of 20 evaluable patients in a dose-related fashion. This study demonstrates that intrapleural administration of an adenoviral vector containing the HSVtk gene is well tolerated and results in detectable gene transfer when delivered at high doses. Further development of therapeutic trials for treatment of localized malignancy using this vector is thus warranted.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Sterman
authors.forename: J
authors.initials: J
authors.lastname: Treat
authors.forename: L A
authors.initials: LA
authors.lastname: Litzky
authors.forename: K M
authors.initials: KM
authors.lastname: Amin
authors.forename: L
authors.initials: L
authors.lastname: Coonrod
authors.forename: K
authors.initials: K
authors.lastname: Molnar-Kimber
authors.forename: A
authors.initials: A
authors.lastname: Recio
authors.forename: L
authors.initials: L
authors.lastname: Knox
authors.forename: J M
authors.initials: JM
authors.lastname: Wilson
authors.forename: S M
authors.initials: SM
authors.lastname: Albelda
authors.forename: L R
authors.initials: LR
authors.lastname: Kaiser
mesh_terms: D000260:Adenoviruses, Human / Q000378:metabolism; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology* / Q000633:toxicity; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D018139:Simplexvirus / Q000201:enzymology* / Q000235:genetics; D017741:Survivors; D013937:Thymidine Kinase / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D013937:Thymidine Kinase; D015774:Ganciclovir