Recombinant DNA Advisory Committee - 12/1-2/94 
whether hepatocellular necrosis results from the gene transfer or conventional therapy. In their written 
response, the investigators note that chemotherapy toxicity is well characterized and can be differentiated from 
vector-related toxicity, Ms. Meyers noted that side effects, such as nausea, will be difficult to differentiate 
between these two treatments. 
Ms. Meyers noted liver cell necrosis occurred in mice through tail vein injection of the vector. How can 
hepatic delivery be compared to tail vein injection? The RAC should review primate hepatic infusion safety 
data before approving the protocol for humans. No side effects can be ruled out as being unrelated to gene 
transfer, including nausea. The investigators should be required to present the results from the ongoing 
primate studies. 
Other Comments 
Responding to Ms. Meyers’ concern about tail vein injection. Dr. Erickson noted that the investigators have 
performed a relevant rat experiment by hepatic artery delivery of the vector. 
Dr. Par km an stated that he shared the same concern about toxicity with Ms. Meyers. The serum chemistry 
analysis of liver enzymes in the mouse experiments is not adequate. Since a mouse is not a permissive host for 
the adenovirus vector, Dr. Parkman preferred to have the study performed in a permissive host, Le., the cotton 
rat. The proposed dose escalation schedule is too aggressive. The rat and primate toxicity studies are critical 
for assessing acute toxicity and chronic hepatitis. Responding to Ms. Meyers’ question about differentiation of 
chemotherapy and vector-related toxicities, Dr. Parkman explained that peak liver enzyme elevation occurs on 
Day 7. Chemotherapy will not be initiated until Day 28; therefore, the effect of such therapy can be easily 
differentiated from acute vector toxicity. Questions regarding chronic hepatitis have to be answered in the 
long-term animal studies. He could not anticipate the outcome of the effect of liver toxicity to the subsequent 
chemotherapy. Dr. Parkman emphasized more data is needed in order to address the issue of acute toxicity. 
Dr. DeLeon noted that a primate model was not required for approval of Dr. dayman’s protocol. Dr. 
Parkman said Dr. dayman’s study involves local vector injection. This proposal involves hepatic artery 
infusion which has the potential for exposing a substantial number of normal cells to the vector. Dr. Smith 
expressed concern about potential toxicity. Drs. Grossman and Woo’s preclinical primate data demonstrated 
brain toxicity at high doses (adenovirus vector). 
Dr. Samulski commented that the proposed vector construct has El (including the coding sequence for protein 
IX), Ela, and Elb deletions. Both Ela and Elb deletions are common to other adenovirus constructs. 
Deletion of the protein IX coding sequence renders this vector more heat sensitive and poses less risk of 
horizontal transmission. He asked the investigators to address the issue of unintended vector spread to other 
organs, e.g., the lung, as observed in the preclinical animal studies. Dr. Samulski suggested that attention 
should be paid to vector construction for the primate experiments, to ensure that the vector is completely 
permissive in that host. He added that a single alteration in the DNA-binding protein coding sequences 
renders the vector more permissive in primates. 
Dr. Doi asked if the timeframe for direct comparison of acute toxicity is comparable for mice and humans. 
Dr. Parkman asked if there is any evidence of vector spread to ovaries or testes in the murine experiments. 
Similar studies should be conducted on primates since this protocol is the first to administer high does of 
adenovirus vector via the hepatic artery. Although systemic vector administration was proposed for Dr. 
Nabel’s protocol (#9306-045), the risk of unintended transduction is higher for this adenovirus vector than Dr. 
Nabel’s nonviral DNA/liposome complex. 
Investigator Response— Drs. Venook and Warren 
Dr. Venook stated that he is a medical oncologist and that Dr. Warren is a surgical oncologist. Dr. Venook 
stated that the murine tissue distribution studies (tail vein injection), demonstrated transgene expression in the 
spleen and adrenal glands but not in the lung. Viral DNA was detected in the lung. Additional information 
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Recombinant DNA Research, Volume 20 
