SPECIFIC ACTIVE IMMUNOTHERAPY OF HUMAN MELANOMA

我们将继续开发主动特异性免疫疗法来治疗 黑色素瘤的一个版本在30%的人中导致了消退 I期试验中的患者，刺激两种细胞介导的 免疫和抗体。四个互补的方法将是 采取的措施：1)优化临床方案，2) 细胞溶解的表型和靶点的鉴定 淋巴细胞被激发，3)血清指标分析 抗体，以及4)鉴定和纯化 由我们的一系列人类单抗识别的抗原。 首先，将进行第二阶段试验，以确定真的 在第一阶段确定的最佳剂量下的应答率，以及 探索类似于最佳免疫方案的计划 老鼠。临床方案的改进将主要通过使用 更丰富、更多样、更纯净的免疫原来源。 具有一种特别感兴趣的裂解物的第一阶段试验将是 已执行。衍生的“多价”制剂的第二阶段试验 从几个黑色素瘤中分离出黑色素瘤细胞 膜，如果它们被证明是免疫原的丰富来源。 最后，将进行大规模的第三阶段随机试验 为了测量显微镜下残留的患者的存活率， 到那时，准备工作被发现是最佳的。我们将监控所有 通过免疫学分析得出结论。细胞溶解的频率 淋巴细胞将通过有限稀释法每两周进行一次测定。 抗体也将通过酶免疫分析和 蛋白免疫印迹。皮肤测试黑色素瘤裂解物和人类白细胞抗原- 治疗前后进行配对对照。我们会 描述细胞溶解淋巴细胞的特征，这似乎是 非经典T细胞，通过冷靶竞争分析与 各种肿瘤和正常细胞。将建立克隆以 最好确定他们的身份和目标。人类白细胞抗原的作用 作为细胞溶解的靶点或共同决定因素的决定因素也将 被探索。用酶免疫分析和吸收分析 免疫印迹试验将被用来观察哪些黑色素瘤抗原 诱导血清抗体，并将抗原定位在 黑色素瘤细胞。猪瘟病毒抗原的生化特性研究 被人类识别的黑色素瘤细胞的内部 将继续使用单抗。重组DNA 技术将被用于克隆抗原，研究它们的 并为未来的疫苗提供提纯材料。

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.