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GENETIC THERAPY BRAIN TUMOR PHASE I INTERIM RESULTS SHOW DECREASE IN TUMOR SIZE; NIH RAC SUGGESTS GENE MARKERS AND VACCINES MAY BE EXEMPT FROM REVIEW

Executive Summary

Genetic Therapy's brain tumor gene therapy shows decreases in tumor size and/or positive changes in tumor consistency in over 60% of the patients treated in an early Phase I trial. Interim results of the Phase I trial, being conducted under an IND held by GTI, were presented Sept. 8 by National Institute of Neurological Disorders and Stroke's Zvi Ram, MD, at the Tenth International Conference on Brain Tumor Research Therapy in Stalheim, Norway. The principal investigator for the trial is NINDS research Edward Oldfield. Five of the eight patients in the trial of adults with recurrent refractory malignant brain tumors demonstrated a response to therapy with Genetic Therapy's murine retrovirus containing the herpes simplex thymidine kinase (HS-tk) gene followed by doses of ganciclovir (Syntex' Cytovene), Ram reported. In the trial, patients received 5 X 10 to 1 X 10 producer cells containing the retroviral vector and gene injected directly into the tumor, followed after seven days by a 14-day course of ganciclovir 5 mg/kg b.i.d. The trial shows that at least some of the patients' tumor cells incorporated the HS-tk "suicide gene" allowing them to be killed by the administration of ganciclovir. The gene is only taken up by cells undergoing mitosis, such as tumor cells, not normal brain cells, which do not divide. Three patients had decreases in tumor size. Four of the five responding patients had positive changes in tumor consistency. The remaining three patients with rapidly emerging glioblastoma progressed in their disease despite the gene therapy, and two of them have died. GTI VP-Development Gerard McGarrity, PhD, called the results "encouraging," adding that it is "still very, very early" to draw any conclusions from the data. McGarrity said the "good news" is that both the gene therapy and ganciclovir were well tolerated by patients. McGarrity made his remarks before the National Institutes of Health's Recombinant DNA Advisory Committee, which met Sept. 9. The committee was asked to re-evaluate a pediatric brain tumor Phase I protocol submitted by St. Jude Children's Research Hospital in Memphis that plans to use the same HS-tk gene and ganciclovir therapy. The pediatric protocol was unanimously approved by the RAC. The Phase I trial, which is under the direction of St. Jude principal investigator Larry Kun, MD, will enroll six children with progressive or recurrent malignant supratentorial brain tumors that are resistant to the standard therapies of surgery plus radiation or chemotherapy. One of the few criticism of the protocol, expressed by RAC member Peter Geiduschek, PhD, University of California-San Diego, was that the study is not sufficiently different from the previous adult protocol to advance the understanding of gene therapy. The NIH RAC also approved a breast cancer protocol that uses GTI's multi-drug resistance (MDR-1) gene to treat patients' precursor hematopoietic stem cells curing autologous bone marrow transplantation. The MDR-1 protein produced by the gene pumps chemotherapeutic drugs out of stem cells before the drugs are able to kill them, thereby reducing the toxic effects of cancer treatment. The study, which is to be conducted under the direction of principal investigator Joyce O'shaughnessy, National Cancer Institute, was previously reviewed by the RAC in December 1992. At that meeting, the RAC asked the investigators to characterize the retroviral construct and producer clone that will be used in the trial. A third protocol involving a GTI-engineered retroviral vector carrying the interleukin-2 gene for the treatment of advanced metastatic melanoma patients was approved conditionally on Sept. 10 by the RAC. The vote was 11 to zero with six abstentions. Under the protocol, devised by principal investigator James Economou, PhD, University of California-Los Angeles, 10 patients will be treated with the IL-2 gene-transduced M-24 cells in an attempt to boost the immune response of cytotoxic T lymphocytes against the cancer. The RAC members requested that the investigators provide HLA typing in advance of infusion of the cells, more information on the characteristics of the M-24 cell line, and perform an assay on the biological activity of the IL-2 produced by the gene. The RAC also approved an Immunex protocol for the use of genetically modified autologous CD8+ HIV-specific T cells in the treatment of HIV seropositive individuals. The vote, taken Sept. 9, was 16 to zero with two abstentions. The protocol, to be administered by Stan Ridell, MD, Fred Hutchinson Cancer Research Center, and Phillip Greenberg, MD, University of Washington, will use CD8+ cytotoxic T lymphocytes transduced by a fusion gene encoding hygromycin phosphotransferase and herpes-derived thymidine kinase to track the in vivo persistence of the T cells transferred to patients. The fusion gene is being provided by Immunex subsidiary Targeted Genetics. Three additional protocols were approved by the RAC during the two-day meeting: a Phase I study of transfected cancer cells expressing the IL-2 gene product in limited stage small-cell lung cancer (conducted by University of Miami researcher Peter Cassileth, MD); a protocol under the direction of Flossie Wong- Staal, PhD, UCSD, that plans to treat HIV-infected individuals with autologous lymphocytes transduced by a ribosome that cleaves HIV-1 RNA; and a pilot study of toxicity of immunization of patients with unresectable melanoma with IL-2 secreting allogeneic human melanoma cells (conducted by Tapas Das Gupta, MD, University of Illinois College of Medicine). The start of an IL-4 gene therapy cancer trial that had been approved in September 1992 by the RAC was announced Sept. 9 by the University of Pittsburgh. In the trial, patients with advanced melanoma, breast, colon and kidney cancer will be injected with their own irradiated fibroblasts genetically modified to carry the IL-4 gene. The investigators, led by Joshua Rubin, MD, plan to enroll 15 to 20 patients in the trial during the first year. The retrovirus used to introduce the IL-4 gene into the fibroblasts is being provided by GTI. In addition to evaluating the gee therapy protocols, the RAC addressed the issue of what protocols might be exempt from RAC review. While the committee deferred further discussion of the subject to their next meeting in December, the RAC members tentatively concluded that the following types of protocols may be exempt from full RAC review: all gene marker protocols using previously approved vectors; a gene therapy with prior RAC approval being used at different sites; and protocols in which cells that have been transduced by a retrovirus will be lethally irradiated. In addition, the RAC suggested that all recombinant products that are intended to provoke an immune response, such as vaccines, should be exempt from RAC review. The RAC members said that all protocols should be reviewed by FDA in as public a manner as possible, such as through advisory committee meetings. Viagene VP Clinical Development and Regulatory Affairs Bruce Merchant, MD, petitioned the RAC in an Aug. 12 letter to exempt future protocols from RAC review of the company's murine retroviral vector encoding HIV-1 genes. The Viagene vector is being used to boost the immune system of asymptomatic HIV-infected subjects. At the meeting, Merchant said Viagene has "plans at the present on the drawing board for five to seven additional protocols" for the HIV immunotherapeutic. He argued that each protocol would have to wait at least five months to undergo RAC review. Merchant said that he is confident that the HIV immunotherapeutic is exempt from RAC review even under current guidelines.
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