Human Gene Therapy Subcommittee - 11/21-22/91 
Dr. Nabel explained that the PLJ vector and the RSV P-globin vector are equally 
effective at mediating tumor regression. In the porcine model, all three vectors induce a 
profound inflammatory response in the arteries following delivery of the H-2K S gene to 
the vessel wall. The porcine model is the most appropriate choice for demonstrating 
efficacy and expression of the vector. Gene expression in human melanoma has been 
studied with Vectors I and II only. However, based on preliminary data, the vector of 
choice would be Vector II. The rationale for proposing all 3 vectors in this protocol is to 
allow for the option of substituting vectors should equal or increased levels of expression 
be observed in the future. 
Dr. Miller asked Dr. Nabel to describe the assays performed to demonstrate that no T 
antigen is made. Dr. Nabel explained how the SV40 poly A sequence was derived in 
fragments. There is an MBO I fragment that is approximately 600 base pairs from 
position 4700 to 4100. This fragment does not have a start signal or the spliced donor 
signals for SV40 large type, but contains the small T antigen coding regions. Dr. Nabel 
said that it was probably more germane for the subcommittee to know that there has 
been extensive in vivo experience, and there is no reason to believe that there are any 
safety concerns. 
Dr. Miller noted that RSV is a monkey virus and asked if there were data demonstrating 
the safety of this vector in mice. Transgenes often cause illegitimate incorporation, 
resulting in transgenic mice that are tumorigenic. Dr. Nabel said that there was no 
possibility that the T antigen could be rescued with these vectors. Dr. Miller stated that 
it is unfortunate that the (i-globin vector does not produce high levels of transfection and 
gene expression compared to the other vectors. Dr. Parkman noted that the HGTS had 
not seen data regarding transfection of melanoma cells with the p-globin vector. Dr. 
Nabel said that he would like to reserve the option to use the P-globin vector should it 
work as well as the other vectors. 
Dr. Miller emphasized that the HGTS would have to make a decision as to whether the 
investigators should be allowed to insert a fragment of the SV40 T antigen into patients. 
In its entirety, this antigen can cause transformation of normal cells that may result in 
disease. Dr. Nabel agreed; however, the in vivo data indicate that the T antigen will not 
be generated. 
Dr. Parkman said that the subcommittee should only approve the use of one vector at 
this time. The investigators could propose a minor modification to the protocol at a 
later date if they wanted to have another vector approved by the HGTS. Dr. Epstein 
said that the subcommittee could recommend approval of a number of vectors if they 
thought there was sufficient justification by the investigators. Dr. Parkman agreed in 
theory, but the subcommittee cannot approve a protocol that states that the vector will 
be defined in the future. Drs. Miller and Epstein agreed that Vectors II and III are safe 
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