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Executive Summary

Viagene's Phase I gene transfer protocol for in vivo therapy to delay or prevent the onset of AIDS in people infected with HIV-1 was unanimously approved by NIH's Recombinant DNA Advisory Committee during its June 7-8 meeting pending the review of confidential formulation information by two committee members. Fifteen asymptomatic patients will be enrolled in the preliminary study, which will evaluate the safety and biologic effects of the proposed gene transfer procedure. The study involves a new approach to delaying AIDS in infected individuals by stimulating killer T-cell response. Viagene filed an IND for the protocol with FDA in May and must await the agency's approval to proceed. Submission of the protocol to RAC was voluntary because the study will not have NIH funding. Japan's Green Cross Corp. is funding the study, which will be conducted by Los Angeles-based Shared Medical Research Foundation, whose founder, Jeffrey Galpin, MD, is the principal investigator. Viagene VP-R&D Steve Mento explained to the committee that the company opted for RAC review because of the expectation that future testing of the gene therapy product will involve NIH-funded institutions and the resulting interest in having RAC involved from the beginning. The protocol involves intramuscular injection of a genetically engineered, non-replicating murine retroviral vector carrying the envelope and rev genes from HIV-1 into HIV-1 infected patients. The hypothesis is that the vector will cause healthy cells to express the HIV-1 envelope protein, which would then induce a cytotoxic T-lymphocyte response above that seen in untreated patients, in the hope that an augmented CTL response will slow or reverse disease progression. Viagene has another HIV gene transfer protocol under way, involving the injection of an ex vivo preparation made from an individual's tissue culture. The company received FDA approval for that protocol in June 1992 and injected its first patient in April. To date, four patients have received injections, and no side effects have been seen, Mento reported. The committee approved a second HIV protocol, sponsored by Gary Nabel, MD, University of Michigan. That protocol involves removing peripheral blood cells from HIV-infected individuals with CD4 T-cell counts of greater than 250 on AZT therapy; selecting the CD4 subpopulation of cells; transducing the cells with either a retrovirus or a plasmid containing a dominant negative form of the HIV-1 rev gene; infusing cells back into donors; and determining the number and longevity of cells. The hypothesis is that cells containing the transdominant negative form of rev will be less able to support HIV replication. The committee also approved a protocol submitted by Nabel for immunotherapy of cancer. The protocol will allow for treatment of 24 cancer patients by direct injection of a DNA/liposome complex encoding the major histocompatibility antigen into tumors. Vical will supply materials for the trial. The protocol is similar to a 12-patient melanoma trial sponsored by Nabel that RAC approved last year ("The Pink Sheet" Feb. 17, 1992, p. 12). The introduction of the MHC protein into the tumor site is designed to trigger the body's immune system to respond to the tumor. The trial approved June 7 differs from the one cleared by RAC last February in four respects, committee reviewer Roy Doi, MD, University of California-Davis, told his colleagues: the new protocol calls for use of a "more efficacious cationic liposome"; it involves "an improved vector design" that includes the beta-2 microglobulin gene, which will increase the antigenic signal to the immune system; it includes "a catheter-based gene delivery system that allows the transduction of a larger percentage of the cells within the tumor microcirculation"; and it will apply "the system to different tumor types." Nabel told the committee that he planned to enroll 12 patients for direct injection of the liposomal formulation into the tumor and 12 for use of the catheter for less accessible tumors. Specific cancers likely to be targeted include colon cancer, renal cell cancer and melanoma, he said. Nabel presented the committee with results from the first five patients treated under his earlier protocol. Direct evidence of gene expression has been found in four of the patients, with evidence of protein expression in the fifth, he said, adding that no adverse effects associated with the treatment have been seen. One of the five patients has shown a mixed response, Nabel told the committee. The new liposomal formulation should allow delivery of much higher quantities of DNA, he added. Vical said June 9 that it plans to take the development of the DNA/lipid complex in-house, assuming Nabel's studies continue to show positive results. Vical said it may file a corporate IND for multicenter trials early next year. Two protocols that would use the human multidrug-resistance (MDR1) gene to render cancer patients' bone marrow resistant to the toxicities associated with chemotherapy were endorsed by RAC during the two-day meeting. RAC approved a Phase I/II protocol presented by Charles Hesdorffer, MD, Columbia University, involving autologous bone marrow transplantation (ABMT) in patients with advanced breast, ovarian and brain cancer. Under the protocol, the removed bone marrow cells (CD34+ cells) would be transduced with the Maloney murine leukemia virus containing the MDR1 gene. High doses of chemotherapeutic agents could then be administered without killing healthy marrow cells. Hesdorffer plans to enroll 10 to 20 patients in the trial. The protocol was deferred by the committee at its last meeting, held March 1-2 ("The Pink Sheet" March 8, T&G-3). In addition, RAC unanimously approved an MDR1 protocol submitted by Albert Deisseroth, MD, M.D. Anderson Cancer Center. The trial will enroll 15 to 20 patients whose bone marrow cells will be transduced with the MDR1 gene during ABMT with the goal of increasing the doses of Bristol-Myers Squibb's Taxol (paclitaxel) that can then be used to treat the cancer. CellPro's Ceprate SC stem cell concentration system will be used in the trial. Other trials cleared by RAC include: a cancer trial proposing to transduce malignant melanoma patients' tumor cells with coding for gamma interferon that had been deferred in March; two ex vivo gene transfer studies for Gaucher's disease, one of which was sponsored by Genetic Therapy, Inc.; a protocol to determine the safety and efficacy of using antisense cDNA transcription of insulin-like growth factor I (IGF-1) in brain cancer patients; and a protocol to inject a vector containing the herpes simplex- thymidine kinase gene supplied by GTI into pediatric malignant brain tumor patients in an attempt to induce tumor regression with ganciclovir (Syntex' Cytovene). The committee deferred two protocols pending submission of further data; one study proposed to study the trafficking patterns of ovarian TIL populations, and the other proposed to use interleukin-2-secreting melanoma cells to immunize malignant melanoma patients. The committee voted to approve an amendment to a trial by Michael Blaese, MD, National Cancer Institute, on Severe Combined Immune Deficiency to allow for treatment of up to five newborns using GTI vectors to transduce stem cells taken from their umbilical cords. The first two infants were treated under the amended protocol in mid-May based on an approval under the committee's procedures to approve "minor" protocol changes without having to go before the full group. A third newborn was treated under the amended protocol June 11. A total of 89 patients have been treated to date in the 30 trials approved by RAC prior to the June 7 meeting, committee member Brigid Leventhal, MD, Johns Hopkins Hospital, said, reporting results from RAC's first survey of investigators in approved trials. The committee will be seeking reports every six months to ensure that trials are proceeding in a timely fashion and that no serious adverse events are emerging. To date, "it appears that...the gene transfer process is going on without a large number of complications," Leventhal reported.

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