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Executive Summary

Targeted Genetics will begin its use of marker gene therapy in AIDS patients "immediately," the company said after the National Institutes of Health's Recombinant DNA Advisory Committee approved the protocol on Feb. 11. The study, to be conducted at the Fred Hutchinson Cancer Center in Seattle, will involve the use of genetically altered CD8 cells in patients undergoing bone marrow transplantation for AIDS- related lymphoma. The CD8 cells will be extracted from the patients, grown in vitro, genetically marked and then reinfused into patients. The marker will track "the cells' viability and persistence after they are administered to the patients" and will include "a mechanism for killing off the cells if side effects from the therapy occur." The trial is a landmark for two reasons: it is the first gene therapy trial approved for AIDS; and it is also the first for a commercial sponsor of gene therapy. The other ongoing gene therapy protocols have been submitted by independent investigators. A commercial firm, Genetic Therapy Inc., has provided vectors for all the previous trials. Cetus has provided one vector for a gene therapy trial. Targeted Genetics, a subsidiary of Immunex, filed an IND for the protocol with FDA in December and received approval in January. Immunex discussed the study protocol and its plans to spin off Targeted Genetics at a recent Hambrecht & Quist meeting in San Francisco ("The Pink Sheet" Jan. 27, p. 6). Immunex announced Feb. 13 that it will "spin off Targeted Genetics as an independent company through an institutional private placement" with Immunex retaining 40% ownership. The use of the RAC review by Immunex as the good news on which to hang a financing also represents a first. It has become commonplace to use FDA advisory committee reviews as the triggers for seeking more money, but this may be the first time that NIH's RAC has been used for the same purpose. RAC expressed enthusiasm for the trial design, particularly the use of the "suicide" gene to abort a potentially hazardous experiment. RAC member Scott McIvor, University of Minnesota, commented in his review of the study that it introduces a new concept of molecular tagging with an "ablative function" that "allows the physician recourse" in the event the cells need to be selectively eliminated from the patient. The committee approved the protocol, adding the condition that the consent form be changed to explain more clearly the composition of the retroviral vector and clarify to the patients that they may not receive benefit from the treatments. The Feb. 10-11 RAC meeting at which the Targeted Genetics protocol was considered had a full agenda with several significant gene therapy protocol approvals. In addition to the first AIDS gene therapy trial, the committee approved the first in vivo gene therapy trial, the first trial of genetically altered stem cells, and an ovarian cancer trial. By a 13-0 vote RAC approved a gene therapy protocol involving the in vivo injection of a DNA/liposome complex for the treatment of advanced melanoma. The DNA encoding for a class I major histocompatability antigen is expected to "help the immune system recognize the tumor" said lead investigator Gary Nabel, University of Michigan Medical Center. RAC member Brian Mannix, President, Buckland Mill Associates, explained that the protocol "represents another important threshold in the development of gene therapy." Mannix commented that RAC should approach decisions concerning gene therapy technology "in manageable, incremental steps." He referred to the Nabel protocol as "a good candidate for the first such in vivo experiment." The transfective agent, Mannix pointed out, a DNA containing liposome, is "not expected to survive in the patient." He concluded that the "risks to the patients are well within reason." Under the protocol, 12 patients with melanoma, who have not responded to any other therapies, will receive injections of the liposome carrying DNA. Mannix noted that all patients will have "a life expectancy of approximately six months." RAC approved a revised adenosine deaminase (ADA) gene therapy protocol by a vote of 11-3. As part of the pre-vote discussion, committee member Brigid Leventhal, Johns Hopkins Hospital, requested a conditional statement that would require the investigators to present RAC with an explanation of their toxicity criteria for formally ending the protocol. Lead investigator Michael Blaese, National Cancer Institute, presented the proposal to treat patients suffering from severe combined immunodeficiency disease (SCID) with infusions of CD34+ autologous peripheral blood cells transduced with a human ADA gene. The infusion would be in addition to the infusions of genetically-modified T lymphocytes that two patients are already receiving. RAC member Leventhal urged the investigators to present the committee with an outline detailing two studies: (1) an examination of the CD34+ cells of the patients to demonstrate transduction of ADA expression; and (2) a test of the patients' immune systems to demonstrate efficacy of the CD34+ ADA reconstituted cells, particularly as compared to the ADA reconstituted T cells. The committee agreed to table the vote on the protocol until Leventhal's conditions were met. Despite the progress shown in the original protocol, Blaese emphasized the need for a revised protocol. Although the patients' immune functions "seem to have reconstituted," Blaese pointed to "holes in the immune repertoire" of patients that "we may not have been able to genetically correct." Co-investigator French Anderson, National Heart, Lung and Blood Institute, reiterated this concern, telling the committee that "these kids...are at risk of imminent death." Leventhal challenged the investigators' decision to use patients already receiving treatment with genetically-altered T cells. Leventhal suggested that this strategy would decrease the researchers' "chance of determining efficacy." Peter Guiduschek, University of California-San Diego, added that if the patients "are doing awfully well," then "that's not the right signal for changing the protocol." A gene therapy protocol for ovarian cancer using modified cancer genes susceptible to ganciclovir, was also approved. Under the protocol, presented by Scott Freeman, University of Rochester, patients would receive injections of ovarian cancer cells modified with the gene for herpes simplex virus thymidine kinase (HSV-TK). After subsequent treatment with ganciclovir, tumor reduction is expected as a result of both the cell-to-cell transfer of the lethality of ganciclovir and a triggering of an immune response by the dying cancer cells. The 10-4 vote in favor of the ovarian cancer protocol represents a re-review of the protocol by RAC. The advisory committee deferred a decision on it at a previous meeting based on concerns about animal models and methods of demonstrating the way the cell-to-cell kill works. Before the RAC vote, FDA Director of the Office of Biotechnology Henry Miller noted that the genetic protocols also have to go through FDA review. He suggested that RAC members on the borderline for approving a protocol should vote in favor with the assurance that FDA also will do a review.

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