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疗法 黑色素瘤，其中一种已导致 30% 的患者消退 I 期试验中的患者，刺激细胞介导的 免疫力和抗体。 四种互补的方法将 采取：1）优化临床方案，2） 溶细胞表型和靶标的表征 引出淋巴细胞，3) 血清靶点分析 抗体，和 4) 表征和纯化 由我们的人类单克隆抗体系列识别的抗原。 首先，将进行第二阶段试验，以建立真正的 在第一阶段确定的最佳剂量下的反应率，以及 探索类似于最佳免疫方案的时间表 老鼠。 临床治疗方案的改进主要是通过使用 更丰富、更多样化、更纯化的免疫原来源。 针对一种特别感兴趣的裂解物的第一阶段试验将是 执行。 “多价”制剂的 II 期试验衍生 然后将用黑色素瘤细胞对几种黑色素瘤进行检测 膜，如果它们被证明是免疫原的丰富来源。 最后将进行大规模III期随机试验 测量具有微观残留物的患者的生存率， 那时发现准备工作是最佳的。 我们将监控所有 通过免疫学测定进行追踪。 溶细胞的频率 将通过有限稀释测定每两周测量淋巴细胞。 还将通过酶免疫测定法连续测量抗体 西方免疫印迹。 使用黑色素瘤裂解物和 HLA 进行皮肤测试 治疗前和治疗后将进行匹配对照。 我们将 描述了溶细胞淋巴细胞的特征，这似乎是 非经典 T 细胞，通过冷靶竞争测定 各种肿瘤和正常细胞。 将建立克隆 最好确定他们的身份和目标。 HLA的作用 作为细胞溶解中的目标或共同决定因素的决定因素也将 被探索。 酶联免疫吸附分析和 西方免疫印迹将用于查看哪些黑色素瘤抗原 引发血清抗体，并将抗原定位于 黑色素瘤细胞。 抗原的生化特征 我们人类识别的黑色素瘤细胞的内部 单克隆抗体将继续。 重组DNA 技术将用于克隆抗原，以研究其 自然并为未来的疫苗提供纯化材料。