II. Research Plan 
Protocol 
A. Specific Aims and Hypotheses 
1. To describe toxicities, if any, and to demonstrate the safety of subcutaneous 
injection of autologous in vitro cultured, transfected and irradiated glial tumor 
cells in patients with glioblastoma multiforme. 
2. To demonstrate the efficacy of injection of autologous in vitro cultured, 
transfected and irradiated glial tumor cells in destruction of native tumor 
and/or in delay to time of recurrence. 
We plan to develop a research program that is expanded beyond these phase I toxicity 
studies. Experiments would be designed to learn if effective down-regulation in the 
expression of IGF-I in transfected human glioma cells will result in up-regulation of the 
T cell mediated immune response similar to that which occurs in the rat model. The 
experimental approach would also be designed to address the question of whether the 
immune response is directed towards both transfected and non-transfected human 
glioma and ultimately to whether it leads to tumor regression and increased length of 
survival. 
B. Introduction 
-Clinical Background 
Malignant glioma Each year in the United States approximately 17,500 patients 
are newly diagnosed with malignant brain tumors(l). Malignant gliomas cause 2.5% of all deaths due 
to cancer and are one of the leading causes of death from cancer in young adults, 15 to 34 years of age 
(2,3). The prognosis for patients with such malignant tumors remains uniformly dismal. The length and 
quality of survival have improved only minimally over the past 20 to 25 years despite developments in 
neurosurgical technique, radiotherapy and chemotherapy (4). Survival in patients with malignant 
gliomas (glioblastoma and anaplastic astrocytoma) with current therapy is 40 to 50 weeks. 5). Radical 
surgery and radiotherapy remain the cornerstone of treatment (6,7). Patients undergoing gross total 
resection and radiotherapy have a median survival of 12 months. Thirty-four percent survive 18 
months or longer (5,8). Radiation directed to the tumor and the surrounding area also prolongs 
survival (5). A very modest contribution is added by conventional chemotherapy (9,10,11,12) 
Glioblastoma multiforme is the most invasive of the astroglial neoplasms with a 
tendency to spread widely throughout the brain. Glioblastoma is very often extensively spread by time 
of diagnosis, leading to unresectability, inadequate local control and a consistently poor prognosis. 
Median survival is less than one year after diagnosis, and 5 year survival is less than 5.5% for this 
tumor (2,13). Clinical features which correlate with improved prognosis include an age of less than 65 
years and a high Kamofsky performance rating at the time of diagnosis (see Attachment A). Although 
malignant glioma remains a fatal disease, significant advances have been made in the treatment of 
other malignant central nervous tumors such as medulloblastoma. Increased recruitment into clinical 
studies will be needed if similar progress is to be made in the treatment of gliomas(14). 
Pathologic classification Gliomas most commonly arise by malignant 
transformation of astrocytes. Prognosis is largely determined by pathologic features. The World 
Health Organization (WHO) system of classification divides these tumors into low -grade 
astrocytoma (low grade gliomas), anaplastic astrocytoma and 6 iioblastoma(high grade gliomas(3,15). 
The Daumas-Deport grading system uses four critieria based on nuclear atypia, mitoses, endothelial 
proliferation and necrosis. The system of grading used at the division of neuropathology of CWRU is a 
modification of these previous systems. 
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