Ganglioside GD2 as Target for Immunotherapy in Melanoma

描述：(申请人提供)本提案的目的是适用于 抗独特型(ID)疫苗治疗III期(切除) 结节阳性)黑色素瘤患者。二唾液酸神经节苷脂GD2高表达 在黑色素瘤细胞上的密度，并将被用作免疫治疗的目标。我们 已经产生了一种鼠源性抗ID单抗1A7(TriGem)，它可以 在功能上模拟GD2，并作为替代蛋白抗原 神经节苷脂。在临床前研究中，小鼠、兔和 TriGem诱导的猕猴抗GD2多克隆抗体及其特异性 T细胞增殖反应提示CD4+T细胞的产生 手机救命。在之前的临床试验中，我们已经证明，患有 晚期转移性黑色素瘤与术后高危黑色素瘤患者 佐剂设置产生针对GD2的主动免疫反应 在使用TriGem进行免疫后。我们证明了一种以免疫球蛋白为主的 与纯化的GD2和GD2特异性结合的多克隆体液免疫应答 GD2阳性细胞介导抗体依赖的细胞毒作用 (ADCC)。接种疫苗的患者在体外也表现出T细胞的增殖 在TriGem面前的回应。47例患者的中位生存期为16个月以上 患有晚期疾病的患者。在69名分期患者中，82%的人 三种疾病均存活，平均随访时间为2年。69个中的25个 大剂量干扰素α-2b治疗III期患者 (HDI)加上TriGem。免疫应答等同于或优于单独使用TriGem 96%的人还活着，80%的人没有疾病。TriGem的毒性 仅限于注射部位的局部反应，偶尔有轻微的 发烧。在这个项目中，我们将进行随机的第三阶段临床试验 其中294例结节阳性局部黑色素瘤患者将 按节点状态分层(IIIA与IIIB与IIIC)，然后随机分配到 使用HDI或HDI加TriGem进行治疗。将对患者进行观察 免疫反应和临床结果。我们将继续测试 一种假说，激发强烈的免疫反应将根除 残留肿瘤细胞，防止转移性疾病的扩散，以及 在术后辅助环境下延长高危患者的生存期。 为实现这一目标，我们提出了四个具体目标。首要目标 这项临床研究的目的是比较HDI和HDI加TriGem的疗效 关于无复发生存。次要目标是比较两种方法对 总体存活率。第三个目标是定量免疫球蛋白的相关性。 抗GD2应答无复发，总存活率高。第四个是 监测毒性。

DESCRIPTION: (Provided by applicant) The objective of this proposal is to apply the anti-idiotype (Id) vaccine approach for the therapy of stage III (resected node positive) melanoma patients. Disialoganglioside GD2 is expressed at high density on melanoma cells and will be used as a target for immunotherapy. We have generated a murine monoclonal anti-Id antibody 1A7 (TriGem) which functionally mimics GD2 and acts as a surrogate protein antigen for the ganglioside. In pre-clinical studies, active immunization of mice, rabbits and monkeys with TriGem induced polyclonal IgG anti-GD2 responses and TriGemspecific T cell proliferative responses suggesting the generation of CD4+ T cell help. In previous clinical trials, we have demonstrated that patients with advanced metastatic melanoma and patients with high risk melanoma in the postsurgical adjuvant setting generated active immune responses against GD2 following immunization with TriGem. We demonstrated a predominantly IgG polyclonal humoral immune response with specific binding to purified GD2 and GD2 positive cells that mediated antibody-dependent cellular cytotoxicity (ADCC). The vaccinated patients also demonstrated in vitro T cell proliferative responses in the presence of TriGem. Median survival was 16+ months for 47 patients with advanced disease. Eighty-two percent of 69 patients with stage III disease are alive at a median follow up of 2 years. Twenty-five of the 69 patients with stage III disease were treated with high dose interferon Alfa-2b (HDI) plus TriGem. Immune responses were equivalent or superior to TriGem alone and 96 percent are alive and 80 percent are disease free. Toxicity of TriGem was limited to local reactions at the site of injection with occasional mild fevers. In this project, we will conduct a randomized Phase III clinical trial in which 294 patients with node positive local regional melanoma will be stratified by nodal status (IIIA vs IIIB vs IIIC) and then randomized to treatment with either HDI or HDI plus TriGem. The patients will be observed for immune responses and for clinical outcome. We will continue to test the hypothesis that elicitation of a strong immunologic response will eradicate the residual tumor cells, prevent the dissemination of metastatic disease, and prolong survival in high risk patients in the post-surgical adjuvant setting. To achieve this goal, we have proposed four specific aims. The primaryobjective of this clinical study is to compare the effect of HDI versus HDI plus TriGem on relapse free survival. The secondary objective is to compare the effect on overall survival. The third objective is correlation of the quantitative IgG anti-GD2 response with relapse free and overall survival. The fourth is to monitor toxicity.