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Results for “Recombinant DNA Advisory Committee”

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PubMed1996

In vivo trafficking of adoptively transferred interleukin-2 expanded tumor-infiltrating lymphocytes and peripheral blood lymphocytes. Results of a double gene marking trial.

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and IL-2 appears to produce dramatic regressions in patients with metastatic melanoma and renal cancer. However, the in vivo mechanism of TIL function is not known. We conducted an UCLA Human Subject Protection Committee, Recombinant DNA Advisory Committee, and FDA-approved clinical trial using genetically-marked TIL to test the hypothesis that these cells have unique, tumor-specific in vivo trafficking patterns. TIL and PBL (as a control effector cell population) were isolated and expanded in parallel in vitro in IL-2-containing medium for 4-6 wk. During the expansion, TIL and PBL were separately transduced with the amphotropic retroviral vectors LNL6 and G1Na. Transduced TIL and PBL were coinfused into patients and their respective numbers measured in tumor, peripheral blood, and normal tissues; integrated provirus could be quantitated and distinguished by DNA PCR. Nine patients were treated (six melanoma, three renal) and received between 4.5 x 10(8) and 1.24 x 10(10) total cells. Both "marked" TIL and PBL could be detected circulating in the peripheral blood, in some patients for up to 99 d after infusion. Marked TIL and/or PBL could be detected in tumor biopsies in six of nine patients as early as day 6 and as late as day 99 after infusion. No convincing pattern of preferential trafficking of TIL vs. PBL to tumor was noted. Moreover, concurrent biopsies of muscle, fat, and skin demonstrated the presence of TIL/PBL in comparable or greater numbers than in tumor in five patients. The results of this double gene marking trial provide interesting insights into the life span and trafficking of adoptively transferred lymphocytes, but do not support the hypothesis that TIL specifically traffic to tumor deposits.

Adult↗
PubMed1995

Recent advances in the application of gene therapy to human disease.

PURPOSE: To review the recent advances in the application of genetic modification strategies to the therapy of human diseases for which a molecular defect is known. METHODS: A computerized data bank search, the minutes of the National Institutes of Health (NIH) Recombinant DNA Advisory Committee published in the Federal Record, and reports of human clinical trials were used as data sources for this review. Clinical trials included in this review were published in the literature or approved by the NIH Recombinant DNA Advisory Committee. STUDY SELECTION: Evaluations of the efficacy of genetic modification strategies in clinical trials in human and in animal models are summarized. The design and outcome of the genetic modification strategies employed are reviewed for 16 marking trials, 16 gene replacement trials for molecular deficiency diseases, 3 chemoprotection and 4 chemotherapy sensitization trials, 11 cancer vaccine trials, 2 antisense oligonucleotide trials, and 3 molecular immunotherapy trials. DATA SYNTHESIS: The marking trials have shown that residual leukemia cells in the infused autologous marrow can contribute to relapse following autologous bone marrow transplants. The use of genetic modification for the replacement of missing or deficient genes in severe combined immunodeficiency, familial hypercholesterolemia, and cystic fibrosis has been associated with encouraging results so far. Clinical genetic therapy trials involving cancer vaccines, antisense oligonucleotides, adoptive immunotherapy with genetically modified T cells, delivery vectors containing interleukin-1 receptor inhibitor for arthritis, replacement strategies for storage diseases, and genetic suppression of human immunodeficiency viral replication are just commencing. CONCLUSIONS: The clinical application of genetic modification techniques has thus far been successful in the beginning phases of this field. These early results suggest that continuation of gene therapy trials designed to correct the molecular changes that lead to disease states in humans is warranted. Evaluation of such clinical trials in the future may be based on the analysis of assays for short-term surrogate endpoints, as well as on the therapeutic outcomes of the trial, such as survival or remission.

Bone Marrow Transplantation↗
PubMed1990

Legal regulation of human gene therapy.

The adequacy of existing legal mechanisms to regulate clinical trials of human gene therapy is examined. Existing legal controls include the federal Guidelines for Research Involving Recombinant DNA Molecules and federal regulations for the protection of human subjects. Another significant mechanism is provided by judicial oversight, i.e., judicial decisions involving recombinant DNA research. Human gene therapy does raise new issues that still must be resolved. At least two weaknesses exist in the present regulatory system: first, Recombinant DNA Advisory Committee (RAC) only has authority over federally funded research, not work done with private support, and second, RAC is not mandated to focus on difficult ethical issues, e.g., germ-line therapy, that arise from human genetic engineering technology.

Advisory Committees↗