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Long-term Follow-up of Patients with Malignant Pleural Mesothelioma Receiving High-Dose Adenovirus Herpes Simplex Thymidine Kinase/Ganciclovir Suicide Gene Therapy

Authors' Affiliations: ¹ Thoracic Oncology Research Laboratory; ² Division of Pulmonary, Allergy, and Critical Care Medicine; ³ Abramson Family Cancer Institute; Departments of ⁴ Surgery, ⁵ Pathology, and ⁶ Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Requests for reprints: Daniel H. Sterman, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania Medical Center, 833 West Gates Building, 3400 Spruce Street, Philadelphia, PA 19014-4283. Fax: 215-662-3226; E-mail: sterman{at}mail.med.upenn.edu.

Purpose: Delineation of the long-term follow-up data on a series of patients with malignant mesothelioma, who received a single intrapleural dose of a nonreplicative adenoviral (Ad) vector encoding the herpes simplex virus thymidine kinase "suicide gene" (Ad.HSVtk) in combination with systemic ganciclovir.

Experimental Design: This report focuses on the 21 patients receiving "high-dose" therapy, defined by an intrapleural dose of vector (1.6 x 10¹³ viral particles), where transgene-encoded tk protein was reliably identified on immunohistochemical staining. In 13 patients, the vector was deleted in the E1 and E3 regions of the Ad; in the other eight patients, the vector had deletions in the Ad genes E1 and E4. Safety, immunologic responses, transgene expression, and clinical responses were evaluated.

Results: Both the E1/E3-deleted vector and the E1/E4-deleted vector were well tolerated and safe, although production of the E1/E4 vector was more difficult. Posttreatment antibody responses against the tumors were consistently seen. Interestingly, we observed a number of clinical responses in our patients, including two long-term (>6.5 year) survivors, both of whom were treated with the E1/E4-deleted vector.

Conclusions: Intrapleural Ad.HSVtk/ganciclovir is safe and well tolerated in mesothelioma patients and resulted in long-term durable responses in two patients. Given the limited amount of gene transfer observed, we postulate that Ad.HSVtk may have been effective due to induction of antitumor immune responses. We hypothesize that approaches aiming to augment the immune effects of Ad gene transfer (i.e., with the use of cytokines) may lead to increased numbers of therapeutic responses in otherwise untreatable pleural malignancies.

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