Overall Aims and Objectives: 
The study was designed to provide information on these aspects of this therapy: 
1 . Is there efficacy associated with the repeated administration of vector producing 
cells followed by GCV treatment in brain tumors? 
2. Is there toxicity associated with the repeated administration of vector producing 
cells followed by GCV treatment in brain tumors? 
3. Does the patient develop any evidence of systemic immunity as a result of the 
repeated injection of murine cells? 
2. Background and Significance 
I. Brain tumors and metastasis: 
Brain tumors are a major cause of morbidity and mortality in the population. New 
primary brain tumors develop in approximately 15,000 adult Americans each year. They 
comprise the third leading cause of death from cancer in persons 15 to 34 years of age (1). 
Recent evidence indicates that the prevalence of primary brain tumors is increasing, 
especially in the elderly (2). The astroglial brain tumors, including the highly malignant 
glioblastoma multiforme (GBM), are the most common primary brain tumors. Despite 
aggressive therapy which includes surgical removal of the tumor and post-operative high 
dose radiation, the prognosis of patients with GBM is very grim with a median survival of 9 
to 10 months (3). Although controversial, neither the quality nor time of survival is 
significantly improved when chemotherapy is added to surgery and radiation (4). When 
glioblastoma multiforme recurs, there is 100% mortality within weeks to a few months. In 
one study, a mean survival of 9 months was found in patients with recurrent GBM who 
underwent a second operation but, a reasonable quality of life in those patients was limited 
to 10 weeks following the recurrent GBM (5). Cerebral metastases are a frequent 
complication of systemic cancer occurring in 25 to 35 percent of the 1.1 million new cases 
of cancer per year in the U.S.(6). In 50% of patients, the metastatic disease is localized to 
the central nervous system (7). The cancers that most frequently metastasize to the brain are 
from melanoma, lung, breast, colorectal and renal cell cancers (8). A subset of patients may 
even be cured of their primary cancers only to succumb to the isolated metastatic disease in 
the brain. Surgery, combined with radiation therapy, is the treatment of choice for a single 
focus brain metastasis that is surgically accessible. Median survival using bimodality therapy 
(surgery and radiotherapy) reaches 40 weeks. In most patients with metastatic disease to the 
brain, multiplicity of the lesions, or their inaccessibility, prohibits surgical intervention and 
limits therapy to radiation alone with a median survival of about 15 weeks (9). 
Recently published work suggests the feasibility of in vivo HS-tk gene transfer for the 
treatment of malignant brain tumors (10). The central nervous system has several advantages 
of safety and efficacy for retroviral mediated in vivo gene transfer. First, retroviral vectors 
only integrate and therefore express vector genes in proliferating cells. In the brain, the 
tumor is the most mitotically active cell, with only macrophage-derived cells, blood cells 
and endothelial cells at minimal risk. Therefore, the possibility of specific transduction of 
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