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GENZYME CYSTIC FIBROSIS GENE THERAPY PROTOCOL USING VICAL CYTOFECTINS

Executive Summary

GENZYME CYSTIC FIBROSIS GENE THERAPY PROTOCOL USING VICAL CYTOFECTINS is among 10 gene therapy protocols that will be reviewed by the National Institutes of Health Recombinant DNA Advisory Committee at its Dec. 2-3 meeting. The Genzyme-sponsored protocol, submitted by Eric Sorcher, MD, and James Logan, MD, University of Alabama-Birmingham, will seek to administer the CF transmembrane conductance regulator gene encapsulated in Vical's cytofectin technology to patients intranasally. The meeting will begin at 9 a.m. on Dec. 2 and 8:30 a.m. on Dec. 3 in Conference Room 6 of Building 31 on the NIH campus in Bethesda, Md. Genzyme licensed the use of cytofectins in gene transfer for cystic fibrosis from San Diego-based Vical in October. Cytofectins are cationic liposomes that Vical maintains will provide a synthetic alternative to viral vectors for in vivo gene delivery. Genzyme has a second cystic fibrosis gone therapy protocol that will come before the RAC in December, for its adenovirus- mediated gene transfer of CFTR to the nasal epithelium and maxillary sinus. The protocol is an extension of the CF study being conducted by Michael Welsh, MD, Howard Hughes Medical Institute, which passed the RAC in December 1992 ("The Pink Sheet" Dec. 7, p. 15). At the December meeting, the RAC will receive an update from NIH researcher Ronald Crystal, NM, on his Phase I study of Genetic Therapy Inc.'s CFTR gene therapy for patients with cystic fibrosis. One patient from the study developed a transient inflammatory response to high doses of the adenovirus-mediated therapy ("The Pink Sheet" Nov. 1, p. 19). The RAC also will consider a Vical-sponsored colon cancer gene therapy protocol for the immunotherapy of advanced colorectal carcinoma by direct gene transfer into hepatic metastases. The study, to be conducted by Joseph Rubin, MD, Mayo Clinic, will use Vical's DNA/liposome complex encoding for the histocompatibility antigen HLA-B7 to trigger the body's immune system to respond to the cancer. The DNA/liposome complex is already being used in melanoma patients in a study being conducted by Gary Nabel, MD, University of Michigan, that was approved at the RAC meeting in June ("The Pink Sheet" June 14, p. 6). A second colon cancer gene therapy protocol being reviewed by the RAC will involve the immunization of colon carcinoma patients with autologous irradiated tumor cells and fibroblasts genetically modified to secrete interleukin-2, to be conducted by Robert Sobol, MD, and Ivor Royston, NM, San Diego Regional Cancer Center. Sobol and Royston submitted a second protocol for review at the December meeting for the immunization of glioblastoma patients with tumor cells genetically modified to secrete IL-2. The researchers gained exceptional compassionate use approval to treat a single glioblastoma patient with the gene therapy in January ("The Pink Sheet" Jan 4, T&G-4). Viagene's second protocol for its in vivo HIV ImmunoTherapoutic (HIV-II Benv/rev-retroviral vector) in HIV- infected patients will receive RAC review in December. The study will be conducted by Richard Haubrich, MD, University of California-San Diego. Viagene's first protocol for the HIV ImmunoTherapeutic cleared the RAC in June. The company was not required to bring that protocol before the RAC because that study did not involve federal funding. A Gaucher's disease gene therapy protocol also will be reviewed by the committee. The protocol, submitted by Friedrich Schuening, MD, Fred Hutchinson Cancer Center, involves retrovirus- mediated transfer of the cDNA for human glucocerebrosidase into peripheral blood repopulating cells of patients with Gaucher's disease. The remaining three protocols are for gene therapies in the treatment of cancers. The committee will consider a protocol for adoptive immunotherapy of melanoma with activated lymph node cells primed in vivo with autologous tumor cells transduced with the IL- 4 gene, submitted by Alfred Chang, MD, University of Michigan Medical Center. Another melanoma protocol was submitted by Mario Sznol, MD, NIH, for B7-transfected lethally irradiated allogenic melanoma cell lines to induce cell-mediated immunity against tumor-associated antigens presented by HLA-A2 or HLA-A1 in patients with stage IV melanoma. In addition, NIH researchers Edward Oldfield, MD, and Zvi Ram, MD, have submitted a protocol for an intrathecal gene therapy in the treatment of leptomeningeal carcinomatosis. Other topics on the RAC agenda include a discussion of what categories of human gene transfer proposals could be approved after an accelerated review by the Office of Recombinant DNA Activities and consultation with one or more of the RAC members. The RAC also will consider proposed amendments to the NIH Guidelines for Research Involving Recombinant DNA Molecules to define those categories of recombinant vaccines that are exempt from RAC review. At the committee's last meeting in September, several RAC members suggested that recombinant vaccines should be exempt from full committee review ("The Pink Sheet" Sept. 13, p. 13).
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