CNS 18 - 6 
gene and remain insensitive to the effects of GCV. Second, all of the transduced 
tumor cells (and retroviral vector producing ceils) should be killed by the host 
immune response and/or GCV treatment eliminating potential concern about 
insertional mutagenesis giving rise to malignant cells. 
This is the first clinical proposal to treat malignant pediatric CNS tumors by in - 
vivo genetic manipulation of the tumor’s genome. 
2.2 Clinical Background 
Brain tumors are a major cause of morbidity and mortality with approximately 
35,000 new cases in all age groups each year in the U.S. They comprise the third 
leading cause of death from cancer in persons 15-34 years of age, and may be 
increasing in prevalence in some populations (1,2). The astroglial brain tumors, 
including the highly malignant glioblastoma multiforme (GBM), are the most 
common primary brain tumors in adults. Despite aggressive therapy which 
includes surgical removal of the tumors and post-operative high dose radiation 
therapy, the prognosis for patients with GBM is very poor with a median survival 
of 9-10 months. (3) Although controversial, it appears that neither the quality nor 
the interval of survival is significantly improved when chemotherapy is added to 
surgery and radiation (4). When GBM recurs, there is a 100% mortality within 
weeks to a few months. In one study, a mean survival of only 36 weeks was 
found in patients with recurrent GBM who underwent a second operation with a 
reasonable quality of life limited to 10 weeks (5). 
CNS tumors are the second most frequent malignancy in children under the age 
of 15 years (6). About 45% of children with CNS tumors die from their disease. 
In children, malignant supratentorial astroglia tumors account for 10-12% of brain 
tumors. Although children have longer survival intervals than adults, (18-24 
months compared to 8-10 months), fewer than 20% remain alive at 3 years. 
When compared to adults, pediatric malignant gliomas have a higher propensity 
for leptomeningeal dissemination. The dominent pattern of failure remains local 
recurrence, present in 90% of cases (7-9). 
The supratentorial embryonal tumors (pineoblastoma, cerebral neuroblastoma and 
primitive neuroectodermal tumors) account for 4-5 % of childhood brain tumors; 
20% 2-year disease free survival with current combined modality therapy is the 
rule. Patients with recurrent disease are rarely salvaged, and quickly die of their 
disease (7,10,11). 
2.3 Proposed Retroviral vector-mediated Treatment of Human Brain Tumors 
The central nervous system has several biologic properties which make it 
appropriate for the study of in-vitro gene transfer therapy. First, the retroviral 
vectors to be used only integrate and express genes in proliferating cells. In adults 
and children over the age of 2 years, tumors comprise the most mitotically active 
group of cells in the CNS; macrophage-derived cells, blood cells and endothelial 
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