Human Gene Therapy Subcommittee - July 29-30, 1991 
with which committee should review the requested information required by the 
provisional approval, and how it would be determined that all criteria had been met. 
Dr. Leventhal suggested that the deadline for the submission of the requested material 
be two weeks prior to the next RAC meeting. This deadline would allow time for 
material to be circulated to the HGTS. Any HGTS member who wishes to provide 
his/her input would have sufficient time to provide it in writing before the RAC 
meeting. There was general agreement among the members on this matter. 
Dr. Walters put the motion to provisionally approve the protocol to a vote. The 
motion passed by a vote of 12 in favor, 0 opposed, and 1 abstention. 
PROPOSED ADDITION TO APPENDIX D OF THE NIH GUIDELINES 
REGARDING A HUMAN GENE THERAPY PROTOCOL ENTITLED: GENE 
THERAPY AS RELATED TO THE IMMUNOTHERAPY OF CANCER 
Dr. Epstein said this is a cancer therapy protocol that is listed as a Phase I trial. The 
intent of this protocol is to modify living tumor cells to alter their immunogenicity and 
thereby affect not only the modified cells, but other tumor cells as well. The 
introduced gene will be injected directly into the tumor; this is not an ex vivo 
manipulation of the cells as in other protocols. The gene is to be introduced into the 
tumor cells via a liposome-mediated mechanism, which is used to facilitate its transfer 
across cell membranes. The viral vector is first combined with lipid containing 
liposomes. This construct is then injected into the tumor where it is eventually 
integrated into the chromosomal DNA. 
Dr. Epstein said the introduction of the gene into tumor cells will modify the tumor 
cell to make it more immunoreactive; there will be an immune response against the 
gene that is introduced, but also against other molecules on the tumor cells. It is the 
immune response against these tumor specific antigens that may affect unmodified 
tumor cells nearby as well as elsewhere in the body. The tumor of interest is malignant 
melanoma, and the gene of interest is a histocompatibility antigen, HLA-B7. The gene 
has been cloned into a retroviral construct, PLJ, which is similar to Moloney murine 
leukemia virus derived vectors. The DNA is not a packaging construct; rather, the 
construct itself is inserted into liposomes. The investigators propose to treat four 
groups of three patients with escalating doses to assess the toxicities of the system, to 
assess the immunogenic response, and to determine if there is an objective tumor 
response. 
Dr. Epstein discussed the animal model system. In one experiment, the DNA-liposome 
construct containing the mouse histocompatibility gene, H2-K, was injected into the 
tumor nodules of six mice. Four out of six mice demonstrated a decrease or delay in 
tumor growth and some type of immunogenic response. In another set of experiments, 
Recombinant DNA Research, Volume 14 
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