Recombinant DNA Advisory Committee - 12/2-3/93 
to the RAC, patient #1 developed a secondary brain tumor following injection of vector 
producing cells (VPC) and subsequent administration of ganciclovir. Some RAC 
members were initially concerned that this secondary tumor may have been related to 
the gene transfer procedure. The first brain tumor was diagnosed as an anaplastic renal 
cell metastasis. When the patient developed a glioblastoma at a site distant from the 
original tumor subsequent to gene transfer, extensive analyses were performed. 
Molecular analysis demonstrated no evidence of the retroviral vector or the VPC in the 
second tumor (glioblastoma). Patient #1 demonstrated progressive disease that led to 
death. Extensive post-mortem studies were conducted, and subsequent analyses 
demonstrated that the first brain tumor was misdiagnosed. The original brain mass was 
not a renal cell carcinoma metastasis, but a primary glioblastoma. Patient #1 had two 
primary tumors, a renal cell carcinoma and a glioblastoma. Subsequent progression of 
the glioblastoma resulted in the patient's death. Dr. Leventhal noted that she reviewed 
the data submitted by the investigators and concurs with this assessment. 
VI. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED: INTRATHECAL GENE THERAPY FOR 
THE TREATMENT OF LEPTOMENINGEAL CARCINOMATOSIS /DRS. OLDFIELD 
AND RAM 
Review-Dr. Smith 
Dr. Walters called on Dr. Smith to present his primary review of the protocol submitted 
by Drs. Edward H. Oldfield and Zvi Ram of NIH, Bethesda, Maryland. Dr. Smith stated 
that the Pis propose to use the herpes simplex virus thymidine kinase (HSV-tk) 
gene/ganciclovir (GCV) strategy that has been previously approved by the RAC for 
other malignancies. Leptomeningeal carcinomatosis is a fatal disease; therefore, a 
probable candidate for gene transfer research. The proposed vector, GITKISvNa, is 
similar to the previously approved construct. The packaging cell line, PAS 17, has been 
approved previously. A total of 20 patients will be entered into the study. Patients will 
receive intraventricular and/or intrathecal injections of VPC. The end points of the 
study are to: (1) assess toxicity (i.e., cerebral spinal fluid (CSF) meningitis symptoms 
and/or obstruction induced by placing up to 8 x 10 9 VPC cells in 120 ml of CSF, and any 
adverse reactions such as the asymptomatic gliosis encountered in the previous trial; (2) 
determine the kinetics and distribution of the VPC following injection into the CSF and 
CSF vector titer; and (3) determine clinical efficacy as assessed by standard tumor cell 
markers and magnetic resonance imaging (MRI). 
Dr. Smith expressed concern about the asymptomatic gliosis that was encountered in the 
investigators' previous brain tumor protocol. He asked the PI to summarize the most 
recent data regarding this observation and any correlations with the proposed study. The 
number of VPC proposed for this study is greater than the number of VPC used for the 
rhesus monkey studies. This larger number of cells may increase the risk of CSF 
blockade and other meningeal complications. The P-galactosidase reporter gene was 
used successfully as a marker to assess gene transfer in the preclinical studies; therefore, 
this reporter gene should yield valuable information about HSV-tk transduction of tumor 
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