SPECIFIC ACTIVE IMMUMOTHERAPY OF HUMAN MELANOMA

人类黑色素瘤的特异性主动免疫治疗

• 批准号: 3173743
• 负责人: Malcolm Stuart Mitchell
• 金额: $ 17.39万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-01-01 至 1987-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3173743
• 关键词: butanols; delayed hypersensitivity; dosage; flow cytometry; human subject; human therapy evaluation; humoral immunity; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; suppressor T lymphocyte; tissue /cell culture; tumor antigens

We will prepare 1-butanol extracts of fresh human melanoma cells to use as an allogeneic "vaccine" for active specific immunotherapy. The melanoma-associated antigens in each extract will be detected by a panel of mouse and human monoclonal antibodies and quantitated by a binding inhibition procedure we have developed. Human monoclonal antibodies will be continually developed from human-mouse and human-human fusions, with regional lymph node cells from melanoma patients as one partner and a nonsecretory mouse (M5) myeloma or a human B or myeloma cell line as the other partner. These human monoclonal antibodies will enable us to determine the presence of epitopes recognized by patients as "foreign", in the butanol extracts used as immunogens. The toxicity and immunological effects of a standard pool of 3 antigenic extracts will be tested in a formal Phase I trial, with metastatic melanoma patients. Two-fold escalations will be performed in each group for a total of 3 levels of dosage, with and without low-dose cyclophosphamide as a potentiator of immunity. Besides noting standard toxicity, we will also measure suppressor T cells by various complementary methods, to determine the possible occurence of this potentially harmful consequence of immunization. Several tests for antibodies to melanoma including immune adherence, protein A mixed hemadsorption and two tests for cytophilic antibodies (LAI and ADCC), will be performed. We have also developed a new titration method based on competitive inhibition of monoclonal antibody binding, with a sensitivity of 1-2 ng of antibody, to measure most sensitively the serum antibody response in the patients. Delayed hypersensitivity will be studied by skin testing with the pool of melanoma extracts. We will also explore limiting dilution analysis of cultivated T cells as a new means of detecting cytolytic antimelanoma T cells, since other tests of cell-mediated immunity have been inconsistently reliable. The developmental aspects of this proposal, with improvement of competitive binding, limiting dilution analysis and suppressor cell methods, in fact constitute an important rationale for the entire study. This closely monitored clinical trial may help to define the most important antigens to include in a "vaccine", leading to their selective use in future studies of specific active immunotherapy for melanoma.

我们将从新鲜的人黑色素瘤细胞中制备1-丁醇提取物，用于 一种用于主动特异性免疫治疗的同种异体“疫苗”。这个 每种提取物中的黑色素瘤相关抗原将通过一组 鼠和人的单抗和结合法定量 我们已经开发了抑制程序。人类的单抗将 从人-鼠和人-人的融合中不断发展， 黑色素瘤患者的区域淋巴结细胞作为一个伴侣和一个 非分泌性小鼠(M5)骨髓瘤或人B或骨髓瘤细胞系 其他合伙人。这些人类单抗将使我们能够 确定是否存在被患者识别为“外来”的表位 丁醇提取物用作免疫原。毒性和免疫学 由3种抗原性提取物组成的标准库的效果将在 转移性黑色素瘤患者的正式I期试验。两重 将在每个组中执行总共3个级别的上报 剂量，使用和不使用低剂量环磷酰胺作为促进剂 豁免权。除了注意标准毒性外，我们还将测量 通过各种互补的方法抑制T细胞，以确定 这一潜在有害后果的可能发生 免疫接种。包括免疫在内的几种黑色素瘤抗体检测 黏附、蛋白A混合血吸附和两种细胞亲和性试验 抗体(LAI和ADCC)，将进行。我们还开发了一种新的 基于单抗竞争抑制的滴定方法 结合，灵敏度为1-2毫微克抗体，以测定大多数 敏感地检测患者血清抗体反应。延迟 过敏性将通过黑色素瘤池的皮肤测试进行研究 萃取物。我们还将探索培养的T细胞的极限稀释分析 细胞作为检测细胞溶解抗黑色素瘤T细胞的新手段，因为 其他的细胞免疫测试一直不太可靠。 这项提案的发展方面，随着竞争力的提高 结合、限制稀释分析和抑制细胞方法，事实上 构成了整个研究的重要理论基础。这么近了 受监测的临床试验可能有助于确定最重要的抗原 包括在“疫苗”中，导致在未来研究中选择性地使用它们。 黑色素瘤的特异性主动免疫治疗。