Recombinant DNA Advisory Committee - 12/1-2/94 
gene therapy protocols is that the preclinical data should correlate directly with the proposed tumor target. 
Different responses will be observed based on the tumor type. Minimal data have been provided to 
demonstrate an antitumor effect in the proposed target cell. Approximately 60% of the data involves 
hepatocellular carcinoma cells, about 30 to 35% involves squamous cell carcinoma, and 5% involves lung 
cancer and brain tumor cells. 
Dr. Par km an noted that the nude mice experiments are invalid. These mice received either a combination of 
human hepatocellular carcinoma cells and PA317 alone or PA317 VPC (HSV-TK vector). Following GCV 
administration, the amount of tumor regression observed with VPC was equivalent to the regression observed 
with non-modified PA317 cells. If the effect observed with the modified and unm odified cells is the same, why 
should patients be subjected to any potential risk relating to the recombinant murine retrovirus? In their 
written response, the investigators state that PA317 cells contain an HSV-TK expression plasmid which could 
elicit a "bystander" effect. Dr. Parkman said that the data do not demonstrate any significant benefit over the 
control VPC PA317 alone. The investigators have recently provided additional data indicating a differential 
effect; however, the difference is not statistically significant. The investigators have performed an additional 
experiment with the NIH3T3TK' cell line (HSV-TK negative), but the results of this experiment are 
inconclusive. 
The investigators have provided data involving human squamous cell carcinoma, a tumor type that is more 
relevant to the protocol. One animal was injected with a combination of 2/3 non-transduced cells and 1/3 
transduced cells in one flank and with non-transduced cells on the contralateral side. After GCV treatment, 
tumors on both sides regressed. The small difference observed in tumor regression between the two flanks 
can be attributed to variability in the number of tumor cells that were injected. The data suggests that GCV 
alone may act as a therapeutic agent for squamous cell carcinoma. 
Dr. Parkman concluded from these data that GCV results in tumor regression by a mechanism that is not 
clearly understood. It remains to be determined whether VPC co-injection is necessary to elicit tumor 
regression. Dr. Parkman said that he would not be comfortable approving this protocol since the preclinical 
data are inconclusive. 
Review— Dr. Ross 
Dr. Ross expressed concern that the proposed study employs the same VPC that have been administered to 
subjects in other protocols that have reported many adverse effects. These adverse effects have been 
attributed to intratumoral injection, biopsies, or rapid rate of VPC infusion. However, the causes for these 
events have not yet been determined. To what extent the adverse effects will be limited to patients with brain 
tumors is unknown. She asked if it is advisable to use the VPC to treat the head and neck tumors. She 
suggested that tumors should be independently evaluated by more than one individual by computer 
tomography (CT) or MRI. Independent blinded tumor measurement would ensure reliability of the data. 
Dr. Ross made several comments in regard to the Informed Consent document: (1) Pronouns should be used 
consistently throughout the Introduction To The Procedures section, (2) The term "response" should be 
replaced with "reduction in tumor size" throughout the Purpose Of This Study section, (3) Tumor evaluation 
should be explained thoroughly in the Screening section, (4) The discriptor "teaspoon" should be added to "5 
ml" and additional biopsy information should be added to the Treatment section, (5) The request for autopsy 
information should be expanded to include specific details about information that will be obtained in the 
Follow-Up section, (6) Phone call follow-up is not adequate, and should be included in the Amount Of Time 
Required For This Study section, (7) Other possible risks, Le., renal impairment, retinal problem, and headache 
should be included in the Risks Of Cytokine Therapy section, (8) The cost of participation should be thoroughly 
explained in the Cost section, and (9) Name and phone numbers of other contacts should be added in the 
Questions section. 
Review-Dr. Motulsky (presented by Dr. Parkman) 
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Recombinant DNA Research, Volume 20 
