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: 3173746
• 负责人: Malcolm Stuart Mitchell
• 金额: $ 16.98万
• 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/3173746
• 关键词: antibody dependent killer cell; butanols; cell mediated cytotoxicity; 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，其中一个版本已经导致30%的 I期试验中的患者，刺激细胞介导的 免疫力和抗体。 四个互补的方法将是 采取：1）优化临床方案，2） 表型和靶点的表征 3）分析血清中的靶点 抗体，和4）表征和纯化的 我们的系列人单克隆抗体鉴定的抗原。 首先，将进行II期试验，以建立一个真正的 在I期确定的最佳剂量下的缓解率，以及 探索类似于最佳免疫方案的时间表， 小鼠 临床方案将主要通过使用 更丰富、更多样化和更纯化的免疫原来源。 将进行一项I期试验，使用一种特别感兴趣的裂解物， 执行。 一项“多价”制剂的II期试验， 从几个黑色素瘤，然后将进行与黑色素瘤细胞 膜，如果它们被证明是免疫原的富集来源。 最后，将进行大规模III期随机试验 测量显微镜下残留患者的生存率， 发现到那时制备是最佳的。 我们将监测所有 通过免疫测定进行跟踪。 细胞溶解的频率 通过有限稀释测定每两周测量一次淋巴细胞。 还将通过酶免疫测定法连续测量抗体， Western免疫印迹。 黑色素瘤裂解物和HLA- 在治疗前后进行匹配对照。 我们将 描述溶细胞淋巴细胞的特征， 非经典T细胞，通过冷靶竞争试验， 各种肿瘤和正常细胞。 克隆将被建立， 最能确定他们的身份和目标 HLA的作用 在细胞溶解中作为靶或共决定子的决定子也将 被探索。 采用酶免疫分析法进行吸收分析， Western免疫印迹将用于检测哪些黑色素瘤抗原 引发血清抗体，并将抗原定位于 黑素瘤细胞 鸡胚抗原的生化特性 黑色素瘤细胞的内部 将继续使用单克隆抗体。 重组DNA 技术将被用来克隆抗原，研究它们的 并为未来的疫苗提供纯化的材料。