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。造成这一失败的原因是多方面的： 肿瘤负荷、耐药性和治疗毒性。试行阶段II 使用免疫疗法或分化诱导剂的研究表明 成功缩小了巨大的肿瘤。慢性阻塞性肺疾病患者的辅助研究 微小的微观疾病很难解释，因为缺乏 随机化的控制武器。由于每个随机试验都需要大量的 患者数量和只有一个治疗变量的测试，它 对于像神经母细胞瘤这样相对罕见的癌症来说，这是一项艰巨的任务。 N6方案旨在测试一种新的联合疗法和 检查新的探针的有效性，以衡量治疗效果。它 打算优化(1)剂量密集型的顺序交付 诱导治疗，随后是(2)单抗(Moab) 免疫疗法。在对诱导治疗的反应进行评估之前 与摩押合并。环境中摩押的抗肿瘤作用 显微镜下的疾病是通过免疫核素和敏感性来评估的。 免疫学加分子探针。此外，我们还将利用 治疗效果度量与剂量相关的回归模型 个别药物的强度，以预测应答率、存活率 和N6可实现的无进展生存持续时间。我们假设 虽然诱导疗法的实际应答率将是没有 好于预期，中位生存期和PFS持续时间 由于免疫治疗，患者的时间将显著延长。 我们的N6试验研究的初步分析已经证明了可行性， 治疗结果与我们的预测一致。我们是 申请资金以继续患者收益并探索免疫 宿主抗肿瘤作用的机制。使用单克隆反独特型 抗体(AB2)，我们将调查(1)抗-抗- 独特型抗体(Ab3)和(2)特异性细胞毒T淋巴细胞 接受摩押治疗的患者。这项临床试验将检验其有效性。 一种新的治疗方法和衡量疗效的新方法-- 开发治疗罕见疾病的新方法的关键要素 疾病。由于GD2在多种人类肿瘤中被发现，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.