Recombinant DNA Advisory Committee - 12/1-2/94 
able to control the intracranial pressure and inflammatory reaction in the human study, and they are convinced 
that the proposed study is safe. 
Dr. Samulski stated that his reservation about Dr. Grossman’s rationale is that the baboon is not a valid model 
to assess the toxicity issue since it is nonpermissive to adenovirus infection. Dr. Woo thanked Dr. Samulski for 
giving the investigators the credit for performing the baboon toxicity study that has not been conducted in 
other brain tumor protocols. Responding to Dr. Samulski’s concern of using the baboon, a nonpermissive 
host, for the experiment. Dr. Woo said that an additional experiment using the permissive cotton rat is 
ongoing. The rats were preimmunized with the wild-type adenovirus by intranasal infusion, and the adenovirus 
vector was then injected into the brain at a dose of 1.5 x 10 9 pfu. Up to 7 days post-vector administration, the 
animals appear to be normal. Neuropathological analysis is planned to be conducted in a few days. Dr. 
Samulski stated that the experiment should be performed with a combination of the vector and GCV since 
there is a synergistic effect. Dr. Woo answered that such an experiment is planned; however, it has not been 
initiated. Dr. Samulski noted that the cotton rat experiment was initiated in response to the reviewers’ written 
comments. 
Mr. Capron inquired that if a similar cotton rat experiment was requested as a stipulation to the approval of 
Drs. Eck and Alavi’s protocol. He asked for clarification as to what would be considered a satisfactory 
outcome from this experiment since Dr. Par km an stated in the previous review that a negative result has to be 
obtained from this experiment while Dr. Noguchi from FDA commented that the cotton rat data is needed, 
but the results do not have to be negative. Dr. Samulski said the RAC now has the benefit of hindsight to be 
more sophisticated on this issue since the investigators have brought in the baboon toxicity data. Dr. David 
Shine, a co-investigator, confirmed that the cotton rat experiment has been performed with 5 immunized and 9 
nonimmunized animals. Responding to Mr. Capron’s question. Dr. Samulski suggested using the following 
adenovirus CF studies as an example of a way to evaluate the present study: Once the toxic dosage is 
identified, the dosage should be adjusted in subsequent studies. Similar relevant toxicity information is not 
available for the present study. Dr. Glorioso stated that there are published reports about destruction of brain 
tissue following adenovirus injection into the brain. Dr. Woo recited the contingencies required for approval 
of Drs. Eck and Alavi’s protocol including negative results to be obtained from intracerebral injections of 
preimmunized cotton rats as scored by either lethality or dysfunction of the CNS. The results of the cotton rat 
experiment has satisfied this requirement in that no lethality nor CNS dysfunction has been observed in these 
animals although the pathological data has not yet been completed. The investigators will submit the data 
once the experiment is completed. 
Dr. Smith noted that the new data from the baboon experiment has shown the synergism of the vector and 
GCV in causing the toxicity, similar experiments should be conducted in the cotton rats both in this protocol 
and, retrospectively, in the previously approved study by Drs. Eck and AlavL 
Dr. Miller was concerned about the adenovirus dosage that caused the brain damage in the published reports 
mentioned by Dr. Glorioso. Dr. Woo said they have performed an experiment with Fisher rats, and no toxicity 
was observed with the proposed vector dose. Dr. Par km an considered the question of what would be 
acceptable as a beneficial approach to brain tumor therapy since there is no therapy for cancer that does not 
kill some normal cells. The major concern is the therapeutic ratio, a criterion to be used in evaluating the 
outcome of the cotton rat experiments. Dr. Samulski said the cotton rat is permissive to adenovirus infection 
and is an appropriate modeL Similar experiments can now be performed in the monkey with an adenovirus 
genetically modified to be permissive in the monkey. Dr. Samulski said the investigators have provided a toxic 
ceiling dose in the anim al model on which to base their human trial. Dr. Chase commented that the number 
of cotton rats in the experiment is appropriate if all the animals are without any toxic effect. 
Dr. Walters asked for clarification if the injection to the brain will provoke less immune reaction. Dr. 
Glorioso said that in brain tumor patients, the blood brain barrier is frequently compromised. 
Dr. Woo explained that the design of the baboon experiment was a result of consultation with FDA officials to 
test for the vector dose that will produce toxicity in animals with and without GCV treatment. In addition. 
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