I. SCIENTIFIC ABSTRACT 
Scientific Abstract 
Gene Therapy for Malignant Mesothelioma 
Malignant mesothelioma is a primary neoplasm of the mesothelial lining of the pleural or 
peritoneal cavity and accounts for approximately 6000 deaths per year. Although virtually all 
patients die within two years of diagnosis, malignant mesothelioma has a number of number of 
characteristics that make it an attractive model to study the feasibility of using gene therapy for 
localized malignancy. First, no effective therapy currently exists. Second, the location in the 
potential space of the thoracic cavity, makes the tumor is uniquely accessible, facilitating 
directed administration of therapeutic agents and subsequent analysis of treatment effects. 
Third, local extension of disease, rather than the development of widespread distant metastases, 
is responsible for the majority of the morbidity and mortality associated with this neoplasm. 
We propose in this protocol, a Phase I trial to assess the safety and feasibility of treating 
patients with malignant mesothelioma by direct delivery of an adenovirus containing the Herpes 
Simplex thymidine kinase gene (HS VTK) into the pleural space, followed by systemic treatment 
with the antiviral drug ganciclovir (GCV). The rationale for this human protocol was based on 
previous successful experiments using the HSVT/C/GCV system transferred via retroviral 
vectors to treat brain tumors and our own preclinical studies in animal models that demonstrated 
the efficacy of the HSVT/C/GCV system using an adenovirus vector in eradicating established 
human mesothelioma tumors growing within the peritoneal cavity of immunodeficient mice and 
pleural cavity of immunocompetent rats. 
In the Phase I protocol, patients will be treated with HSVT/C-expressing replication deficient 
adenovirus and followed for a) evidence of HSVT/C gene transfer and expression, b) 
immunological responses to HSVT/C or adenoviral proteins, and c) toxicity. Adult patients with 
advanced malignant mesothelioma who are considered acceptable candidates for two thorocoscopic 
procedures will be considered. After thoroscopic confirmation of diagnosis, a suspension of 
virus will be delivered into the pleural space via a chest tube. Tumor biopsies will be harvested 
for analyses by follow-up thoracoscopy 3 days after instillation of virus. At that time, GCV will 
administered by intravenous infusion for 14 days. Patients will subsequently be carefully 
evaluated using clinical, laboratory, and radiographic analyses. 
These studies will provide the scientific and clinical foundation for a future Phase II clinical 
trial for the treatment of mesothelioma. In addition, information will be obtained that will be 
useful for the planning of additional clinical trials focused on the treatment of other localized 
malignancies such as brain tumors, ovarian and bladder carcinomas, and metastatic disease to the 
meninges. 
Recombinant DNA Research, Volume 20 
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