CNS 18 - 5 
1.0 OBJECTIVES 
This is a collaborative Phase I trial whose goals are: 
1.1 To determine the safety of the implantation of xenogeneic vector-producing cells 
in pediatric patients with recurrent primary supratentorial malignant tumors. 
1.2 To determine if ganciclovir administration is associated with a diminution in size 
of brain tumors following HS tk gene transduction. 
2.0 BACKGROUND 
2.1 Prdcis 
Malignant brain tumors are responsible for significant morbidly and mortality in 
both pediatric and adult populations. The common malignant supratentorial 
tumors in children, including malignant gliomas and embryonal tumors, are an 
enormous therapeutic challenge. Despite radical surgery, high dose radiotherapy 
and, in some cases, chemotherapy, outcome remains poor. Survival of most 
patients from the time of diagnosis is measured in months; recurrence is 
associated with a life expectancy of weeks. 
In an attempt to improve this grim prognosis of patients with malignant brain 
tumors, a novel approach is proposed in pediatric patients as part of a 
collaborative clinical trial being done in adults by investigators from the Surgical 
Neurology Branch, NCI and NTH. If this approach is successful, we will succeed 
in incorporating a gene conferring drug sensitivity into brain tumor cells. This 
will be done by direct injection of a producer cell line which actively produces 
a retroviral vector carrying the desired drug sensitivity gene, HS-tk. 
The producer cell is an NIH 3T3 (mouse fibroblast) cell that has been genetically 
engineered to produce transducing retroviral vector continually. Such vectors are 
capable of transferring foreign DNA into mammalian cells. The vector to be 
used in this study has been engineered to incorporate the new genetic material 
stably into the genome of the transduced host cell. The protein encoded by the 
new gene is the herpes simplex virus enzyme thymidine kinase, HS-tk, which 
sensitizes actively dividing tumor cells to an antiviral drug (ganciclovir, GCV) 
which is a substrate for the HS-tk. Ganciclovir is then given in an attempt to kill 
all transduced tumor cells. The form of the thymidine kinase enzyme normally 
present in mammalian cells has very low affinity for GCV. Therefore, only cells 
transduced by the vector and expressing the viral HS-tk gene are expected to be 
killed by GCV. Systemic toxicity is not expected. This type of in vivo gene 
transfer has several unique features. First, these retroviral-vectors were 
engineered to integrate and express the genes they carry only in cells actively 
synthesizing DNA. Therefore, surrounding non-proliferating normal brain tissue 
present in those over 3 years of age should theoretically not acquire the HS-tk 
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Recombinant DNA Research, Volume 18 
