SPECIFIC ACTIVE IMMUNOTHERAPY OF HUMAN MELANOMA

人类黑色素瘤的特异性主动免疫治疗

• 批准号: 3173747
• 负责人: Malcolm Stuart Mitchell
• 金额: $ 16.72万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1990-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3173747
• 关键词: antibody dependent killer cell; butanols; cell mediated cytotoxicity; cell mediated lymphocytolysis test; complement; cytolysis; delayed hypersensitivity; dosage; flow cytometry; genetic recombination; human subject; human therapy evaluation; humoral immunity; immunologic skin test; laboratory mouse; major histocompatibility complex; melanoma; molecular cloning; monoclonal antibody; neoplasm /cancer immunodiagnosis; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; suppressor T lymphocyte; surface antigens; tissue /cell culture; tumor antigens

We will continue to develop active specific immunotherapy for melanoma, one version of which has caused regression in 30% of patients in a Phase I trial, stimulating both cell-mediated immunity and antibodies. Four complementary approaches will be taken: 1) optimization of the clinical regimen, 2) characterization of the phenotype and targets of the cytolytic lymphocytes elicited, 3) analysis of the targets of the serum antibodies, and 4) characterization and purification of the antigens identified by our series of human monoclonal antibodies. First, Phase II trials will be performed to establish a true response rate at the optimal dose determined in Phase I, and to explore a schedule resembling an optimal immunization schema in mice. The clinical regimen will be improved mainly by the use of enriched, more varied, and more purified sources of immunogens. A Phase I trial with one lysate of particular interest will be performed. A Phase II trial of a "polyvalent" preparation derived from several melanomas will then be conducted with melanoma cell membranes, if they prove to be an enriched source of immunogens. Finally, a large scale Phase III randomized trial will be conducted to measure survival in patients with microscopical residua, with the preparation found to be optimal by then. We will monitor all trails by immunological assays. The frequency of cytolytic lymphocytes will be measured biweekly by limiting dilution assays. Antibodies will also be measured serially by enzyme immunoassay and Western immunoblotting. Skin tests with melanoma lysates and HLA- matched controls will be done before and after treatment. We will characterize the cytolytic lymphocytes, which appear to be nonclassical T cells, by cold target competition assays with various tumors and normal cells. Clones will be established to best determine their identity and targets. The role of HLA determinants as targets or co-determinants in cytolysis will also be explored. Absorption analysis with enzyme immunoassay and Western immunoblotting will be used to see which melanoma antigens elicit serum antibodies, and to localize the antigens in the melanoma cell. Biochemical characterization of the antigens in the interior of the melanoma cell that recognized by our human monoclonal antibodies will be continued. Recombinant DNA technology will be used to clone the antigens, to study their nature and to provide purified materials for future vaccines.

我们将继续开发主动特异性免疫治疗