Human Gene Therapy Subcommittee - July 29-30, 1991 
or just the lesion at the injection site. She asked if they plan to monitor for the 
possible development of autoimmunity. 
Dr. D. Miller said that the issue of possible germ line transfer should be addressed. 
The PCR data need to be examined. Are investigators are planning to use the whole 
PU plasmid? This plasmid contains the Polyoma virus T antigen gene which is a 
strong transforming gene. 
Dr. Nabel responded that he is not relying on any one animal model for these systems. 
In fact, he has looked at about four or five different animal models. The experimental 
approach uses the power of the immune system to reject tumors that would otherwise 
grow in vivo by taking naturally occurring tumors and introducing recombinant genes 
into them as they grow in vivo. The major goal for Phase I is to determine the safety 
of this proposed method of treatment and the correct dosage for the patients. In later 
studies, the primary goal will shift to therapeutic efficacy. It is quite possible that in 
the process of determining the safety of this treatment and the correct dosage, there 
may be therapeutic effects for the patient. To assess this, the size of the tumor will be 
monitored locally by noninvasive imaging as well as examination of distant tumor sites. 
Patients will be staged prior to the treatment and will subsequently be staged at two 
four-week intervals during treatment. The local effects of the tumor and any 
therapeutic effects at the various doses will be assayed. Preliminary animal data 
suggest that therapeutic effects are often achieved with doses that would not be 
expected to be toxic in vivo. 
Dr. Nabel noted that there have been multiple trials in humans using liposomes to 
deliver drugs to patients. The potential advantages of this system include the use of a 
non-viral vector that is designed to be incapable of replicating. Another advantage of 
this method is the simplicity of the treatment. There is only one direct injection to 
administer. The protocol was focused on cutaneous melanoma to avoid any invasive 
procedures with the patients. The recombinant gene can be delivered directly to the 
tumors, and biopsies can be easily obtained to examine gene expression. The effects of 
treatment will be shown without performing drastic surgical procedures. Also, there 
are sensitive and accessible indicators of recombinant gene expression in vivo in the 
tissue, and immunologic parameters can also be analyzed. In the event that there is 
some aberrant expression of the recombinant gene in this system, the expression is 
designed to be self-limited. Any cell that makes the gene is going to be recognized by 
the immune system and rejected The treatment's effects are readily quantitated in 
terms of tumor size, immune response, and the presence of the protein. Lastly, there 
are not many treatment options for this otherwise fatal disease. 
Dr. Nabel presented data from the experimental system illustrating that it is possible to 
use catheter delivery systems to introduce recombinant genes into the vessel wall by 
either using retroviruses or lipofection. Class I histocompatibility antigens are among 
Recombinant DNA Research, Volume 14 
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