Recombinant DMA Advisory Committee - 6/9-10/94 
capable of glycosylating the CEA appropriately and are recognized by a panel of specific 
antibodies. An immunological response is induced which is the ultimate functional test. 
Dr. Curiel explained that Dr. Schlom has demonstrated antitumor efficacy of vaccinia- 
CEA in mice with low tumor burdens. 
In response to Dr. Zallen's question. Dr. Curiel said that the RAC has previously 
approved studies in which injected liposome DNA distributes systemically. Preliminary 
PCR assays indicate that as few as 5 DNA copies per mg of tissue are detectable one 
day following injection. DNA was detectable at the injection site, tongue, and gonads of 
animals. Seven days following injection, DNA was detected only in the tongue. This 
result suggests that if DNA localizes beyond the injection site, there is no persistent 
expression. In regard to transduction frequency. Dr. Curiel explained that the 1 % 
frequency described in the protocol is based on published data and not derived fi’om 
experiments conducted in his laboratory. 
In response to Dr. Post's concerns. Dr. Curiel stated that consensus in the literature 
seems to be that the basis of persistence is not integration. Mixing experiments involving 
integrated and nonintegrated genes have been conducted by John Wolfe and published 
data demonstrates that a single integrated copy can be detected in 10^ to 10^ cells. Dr. 
Post stated that although he was unaware of the sensitivity data referred to by Dr. 
Curiel, a low level of DNA integration should be an acceptable risk. 
Dr. Lobuglio of the University of Alabama explained that Dr. Schlom's Phase I vaccinia- 
CEA trial involves subjects with high tumor burden. There was no evidence of toxicity 
up to 10^ virus particles per site. Immunologic response data is not yet available. Dr. 
Lobuglio stated that he has been contracted by Dr. Schlom's group to conduct a second 
vaccinia-CEA trial involving subjects with low tumor burden. This second trial will 
include cytoxan administration and establish evidence of immune response. The basis 
for the proposed plasmid DNA study is preliminary animal data demonstrating that CEA 
is immunogenic and can safely produce both immunoprotection and therapy. 
Dr. Lobuglio explained that the monoclonal antibodies have been directed to the peptide 
portion of the molecule. The murine model demonstrated that intramuscular injection of 
this polynucleotide vaccine resulted in an immune response to the human CEA antigen. 
The presumption is that the human molecule contains the epitopes that are the target of 
the immune response. 
The issue of breaking tolerance by immunizing an individual with a tolerant antigen is an 
overriding issue in tumor immunology. Data does not exist relating to the question of 
CEA immunogenicity in humans. Published data indicate that an immune response to a 
fetal antigen (not CEA) has been observed in humans. 
The term "vaccine" has been changed to "immunization" and "augmentation" throughout 
the protocol in response to concerns about vaccines inferring disease prevention. There 
is increasing evidence in the literature that post tumor immunization can produce a 
detectable immune response. 
Recombinant DNA Research, Volume 19 
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