Recombinant DNA Advisory Committee - 2/10-11/92 
created and processed. The peptide fragments from these foreign molecules are presented 
on self MHC genes, Class I and II. Initially, there is a phase where these foreign MHC 
genes are recognized within the substance of the tumor as being foreign which induces an 
immune response. Subsequently, there is a substantial local cytokine release. This 
endogenous release of cytokine enhances the ability of the immune system to process 
tumor antigens. This mechanism allows these native tumor antigens to be presented more 
efficiently to the immune system and then to be lysed by CD8(+) T-cells. Currently, 
cytokines are being administered in combination with the foreign genes to determine if a 
more effective response can be elicited. 
Experiments have been conducted in normal mice where either the CD4 subset or the 
CD8 subset of T lymphocytes is depleted. Protection is lost when the CD8 subset is 
depleted. The final control experiment was designed to ask whether deletion of the 
polymorphic region of the Class I gene would affect protection. Presumably, the immune 
response is found in the polymorphic region. Indeed, deletion of this region yielded no 
protection when compared to the wild-type controls. 
Dr. Nabel then summed up the advantages of their research: (1) a non-viral vector is 
being used; (2) the form of treatment is relatively simple; (3) a liposome complex 
prepackaged in sterile vials is used; (4) safety and toxicity tests have shown no 
complications; (5) the injection is not invasive, just intratumor; (6) sensitive indicators of 
recombinant gene expression in vivo are available; (7) the expression of the recombinant 
gene is self-limited; (8) there is no chance for unregulated expression of a growth 
stimulatory gene; and (9) there are not many other therapeutic options for this patient 
population. 
Dr. Nabel described the implications of this research and future goals. A catheter delivery 
system will be used to introduce the gene into the blood supply of the tumor. The 
catheter will allow access to metastases and focal lesions. Adjuvant cytokine 
administration will be used to further amplify the immunologic process. Anti-angiogenic 
factors will be used to inhibit the effect of normal angiogenic gene products. Tumor 
antigens will be observed for their effect on the immune response in vivo. The ultimate 
goal is to be able to introduce these beneficial genes into patients at a time when the 
genes can be most beneficial, either before the patients have a tumor or very early in the 
life of the tumor. In conclusion. Dr. Nabel said that these experiments demonstrate that 
not only can an immune response be initiated against a tumor, but a systemic immunity 
against the tumor can be achieved which can be transferred from one animal to another. 
Dr. Nabel addressed a question raised by the HGTS concerning the form in which DNA 
enters the cell. Dr. Nabel responded that it is episomal. Dr. Haselkorn asked Dr. Nabel 
if the DNA would be linearized. Dr. Nabel said that no plans had been made to linearize 
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