Recombinant DMA Advisory Committee - 6/9-10/94 
Dr. Lobuglio explained that Dr. Schlom administered vaccinia-CEA to mice 7 days 
following tumor cell implantation because tumor growth was rapid enough to become 
palpable and reach end stage in 28 days. Conversely, 10 to 14 days are required for gene 
expression by muscle cells in vivo. This time-frame between vaccine administration and 
tumor inoculation was a major constraint to testing this therapy. 
In addressing the RAC's concern about compensation for research-related injury, Dr. 
Lobuglio stated that "all of the normal responsible issues are in place" regarding 
compensation for negligence. Only compensation for compheations arising from the 
research are excluded. This exclusion will be clearly presented to all subjects. 
In response to concerns about possible toxicity of circulating CEA and its immune 
complexes. Dr. Lobuglio said that no evidence of toxicity has been observed in subjects 
with circulating CEA receiving up to 1 gram of anti-CEA monoclonal antibody. One of 
the endpoints of the proposed study is to evaluate tissue injury resulting from an immune 
response to CEA. No such injuries have been observed in the vaccinia-CEA study. The 
proposed polynucleotide vaccine strategy is to overcome the diminished immune 
response to immunogens encoded by vaccinia which can occur in subjects previously 
exposed to vaccinia. In regard to Dr. Haselkom's question about bovine mucin. Dr. 
Lobuglio stated that he was not knowledgeable about such data. 
Other Comments 
Dr. Parkman commented that the RAC has consistently held investigators to the 
standard that preclinical evidence must be demonstrated on established tumors. The 
only data presented by the investigator involved a preimmunization model. Dr. Lobuglio 
agreed but stated that the proposed strategy was similar to that of the vaccinia trials. 
Dr. Post commented that a murine model may be irrelevant for the proposed study. Dr. 
Parkman noted cytokine trials in which animals have received both murine and human 
cDNA's. The investigator has based his hypothesis that this strategy will provide a better 
immune response than the vaccinia study without providing the necessary preclinical 
data. Dr. Lobuglio responded that an alternative, not necessarily better, method is 
proposed to achieve the desired outcome. The only way to evaluate the relative merits 
of the proposed study is to perform the human experiment. Dr. Parkman reiterated that 
preclinical evidence has not been provided demonstrating the efficacy of this treatment 
against metastases, the RACs usual standard. If such studies are not technically 
possible, then the RAC should determine the next level of criteria. 
Dr. Straus stated that the proposed direct DNA injection approach is inherently safer 
than the vaccinia approach; however, there is a lack of preclinical data to support this 
rationale. He recommended that the murine CEA gene should be used in a murine 
model. Dr. Miller said that although there is a lack of scientific evidence to support the 
proposal, the lack of data should be weighed against the potential risk from a 
recombinant DNA aspect. Since the proposed plasmid does not contain any viral 
elements, there is no danger of recombination. The RAC could reduce their standards 
for such innocuous trials. Dr. Chase agreed that the major purpose of this committee 
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