NOVEL COMBINATION THERAPY OF STAGE IV NEUROBLASTOMA

超过80%的IV期神经母细胞瘤儿童无法通过 标准疗法失败的原因有很多： 肿瘤负荷、耐药性和治疗毒性。试验阶段二 使用免疫疗法或分化诱导剂的研究显示， 成功缩小巨大肿瘤。辅助治疗研究 微小的微观疾病很难解释，因为缺乏 随机对照组。由于每个随机试验都需要大量的 患者数量和仅一个治疗变量的检验， 对于像神经母细胞瘤这样相对罕见的癌症来说是一项艰巨的任务。 N6方案旨在测试一种新的联合疗法， 以检验新探针测量治疗效果的有效性。它 旨在优化（1）剂量密集型 诱导治疗，然后（2）单克隆抗体（MoAb） 免疫疗法诱导治疗的反应在 与MoAb合并。单克隆抗体的抗肿瘤作用 显微镜下的疾病是通过免疫闪烁成像和敏感的 免疫学和分子探针。此外，我们将利用 将治疗效果测量与剂量相关的回归模型 单个药物的强度，以预测反应率，生存率 和N6可达到的无进展生存期。我们假设 虽然诱导治疗的实际反应率不会 中位生存期和PFS持续时间好于预期， 因为免疫疗法，患者的寿命将显著延长。 对我们的N6试点研究的初步分析证明了可行性， 治疗结果与我们的预测一致。 我们 申请资金，以继续增加患者人数，并探索免疫 宿主抗肿瘤作用的机制。使用单克隆抗独特型 抗体（Ab 2），我们将研究（1）抗-抗- 独特型抗体（Ab 3）和（2）特异性细胞毒性T淋巴细胞， 用MoAb治疗的患者这项临床试验将测试 一种新的治疗方法和衡量疗效的新方法-- 发展治疗罕见疾病新模式的关键要素 疾病 由于GD 2存在于多种人类肿瘤中，这些结果 可能对其他同样难治的癌症有治疗意义。

More than 80% of children with stage IV neuroblastoma are not cured by standard therapies. There are multiple reasons for this failure: large tumor load, drug resistance and treatment toxicities. Pilot phase II studies using immunotherapy or differentiation inducers have shown limited success in shrinking bulky tumor. Adjuvant studies in patients with minimal microscopic disease are difficult to interpret because of the lack of randomized control arms. Since each randomized trial requires a large number of patients and the testing of only one treatment variable, it becomes a daunting task for a relatively rare cancer like neuroblastoma. The N6 protocol has been designed to test a novel combination therapy and to examine the validity of new probes to measure treatment efficacy. It intends to optimize the sequential delivery of (1) dose-intensive induction therapy, followed by (2) monoclonal antibody (MoAb) immunotherapy. The response to induction therapy is assessed prior to consolidation with MoAb. The anti-tumor effect of MoAb in the setting of microscopic disease is evaluated by immunoscintigraphy and by sensitive immunological plus molecular probes. In addition, we will utilize regression models which correlate measures of treatment efficacy with dose intensities of individual drugs, to predict the response rate, survival and progression-free survival durations achievable with N6. We hypothesize that while the actual response rate of the induction therapy will be no better than predicted, the median survival and PFS durations among patients will be significantly longer because of the immunotherapy. Preliminary analysis of our pilot N6 study has demonstrated feasibility, and the treatment results have agreed with our projections. We are requesting funding to continue patient accrual and to explore the immune mechanisms of host antitumor effects. Using monoclonal anti-idiotypic antibodies (Ab2), we will investigate the presence of (1) anti-anti- idiotypic antibodies (Ab3) and (2) specific cytotoxic T-lymphocytes in patients treated with MoAb. This clinical trial will test the validity of both a new treatment approach and the novel methods to measure efficacy -- critical elements in the development of new modalities for curing rare diseases. Since GD2 is found on a variety of human tumors, these results may have therapeutic implications for other equally refractory cancers.