IMMUNIZATION OF MELANOMA PATIENTS WITH GANGLIOSIDES

用神经节苷脂对黑色素瘤患者进行免疫接种

• 批准号: 3180621
• 负责人: PHILIP O. LIVINGSTON
• 金额: $ 16.07万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3180621
• 关键词: astrocytoma; combination cancer therapy; cytotoxicity; delayed hypersensitivity; drug administration rate /duration; drug administration routes; gangliosides; human subject; human therapy evaluation; inflammation; liposomes; lymphadenectomy; melanoma; monoclonal antibody; neoplasm /cancer classification /staging; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; astrocytoma; combination cancer therapy; cytotoxicity; delayed hypersensitivity; drug administration rate /duration; drug administration routes; gangliosides; human subject; human therapy evaluation; inflammation; liposomes; lymphadenectomy; melanoma; monoclonal antibody; neoplasm /cancer classification /staging; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine

Three cell surface antigens expressed on melanomas are now available in purified form, the gangliosides GD2, GD3 and GM2. All three serve as differentiation antigens for different subsets of cells of neuroectodermal lineage. Both GD2 and GM2 are known to be potentially immunogenic in man as they have been identified by a variety of human sera. The clinical relevance of GD3 has been demonstrated by inflammatory reactions and major clinical responses in 3 melanoma patients treated with anti-GD3 monoclonal antibody (R24). We have however, been unable to develop consistently immunogenic vaccines in man or in the mouse using whole cells or cell lysates expressing these gangliosides. Consequently, we have explored the effect of purified GM2 and GD2 vaccines in the mouse and have identified approaches that consistently induce an antibody response. The success of these murine trials has encouraged us to proceed with similar trials in Stage II melanoma patients. In our initial 3 trials, none of 6 patients immunized with GM2 alone produced antibody but 5 of 11 patients immunized with GM2 plus BCG or GM2 plus Salmonella minn. mutant R595 have produced antibody reactive with GM2 (median titer 320). These sera mediate complement dependent cytotoxicity on human melanoma and astrocytoma cells with human complement. ITLC confirmed that they react exclusively with GM2. The approaches proposed here are (and will continue to be) based on the results of these ongoing studies in the mouse. In intitial trials we will change the dose, schedule and route of administration of GM2 plus BCG or R595 or both to further increase the anti GM2 response rate. Subsequent trials will test other vaccines such as liposomes containing GM2 and GM2 covalently attached to BSA or KLH. Stage II melanoma patients will be vaccinated after, or before and after, lymphadenectomy in small groups and their serological reactivity and delayed hypersensitivity reactions to the relevant gangliosides tested. The immunized lymph nodes removed at surgery will be used to produce human monoclonal antibodies. Approaches provoking a consistent serological or DTH responses will be used with GD2 and GD3, and subsequently with the three gangliosides together. Vaccines producing a consistent response in Stage II patients will be used in patients with measurable disease to gauge their effect on immune responses in the face of more advanced disease.

现在在黑色素瘤中表达的三种细胞表面抗原 纯化形式，神经节GD2，GD3和GM2。 这三个都是 分化抗原的神经外科细胞的不同亚群 血统。 已知GD2和GM2在MAN中具有潜在的免疫原性 正如它们被各种人类血清所识别的那样。 临床 GD3的相关性已通过炎症反应和主要 用抗GD3单克隆治疗的3例黑色素瘤患者的临床反应 抗体（R24）。 但是，我们无法始终如一地发展 使用全细胞或细胞的人或小鼠中的免疫原性疫苗 表达这些神经节的裂解物。 因此，我们探索了 纯化的GM2和GD2疫苗在小鼠中的效果并已鉴定 始终诱导抗体反应的方法。 成功的成功 这些鼠试验鼓励我们继续进行类似的试验 II期黑色素瘤患者。 在我们最初的3次试验中，没有6例患者 单独使用GM2免疫可产生抗体，但11例患者中有5例免疫 使用GM2加BCG或GM2加Salmonella Minn。突变体R595产生了 抗体与GM2反应性（中值320）。 这些血清介导 对人黑色素瘤和星形细胞瘤细胞的补体依赖性细胞毒性 与人类的补充。 ITLC确认他们仅反应 GM2。这里提出的方法是（并将继续） 这些正在进行的研究中的结果。 在实力试验中，我们 将更改GM2加BCG的剂量，时间表和途径 或R595或两者都进一步提高抗GM2响应率。 随后的 试验将测试其他疫苗，例如含有GM2和GM2的脂质体 共价连接到BSA或KLH。 第二期黑色素瘤患者将是 小组中的淋巴结清扫术后接种后或之后接种疫苗 它们的血清学反应性和延迟对 相关的神经毒剂测试。 手术时去除的免疫淋巴结 将用于产生人类单克隆抗体。 方法令人发指 GD2和GD3将使用一致的血清学或DTH反应， 随后将三个神经节一起使用。 疫苗生产 在II期患者中，将使用一致的反应 面对 更晚期疾病。