NOVEL COMBINATION THERAPY OF NEUROBLASTOMA

神经母细胞瘤的新型联合疗法

• 批准号: 2467955
• 负责人: NAI-KONG V CHEUNG
• 金额: $ 30.48万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2467955
• 关键词: antiantibody; antiidiotype antibody; athymic mouse; cellular immunity; child (0-11); clinical research; clinical trial phase I; combination cancer therapy; cytotoxicity; dosage; human subject; human therapy evaluation; humoral immunity; laboratory rat; metastasis; minimal residual disease; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neuroblastoma; pediatric neoplasm /cancer; pediatric pharmacology; polymerase chain reaction

DESCRIPTION: (Applicant's Abstract) Using combination chemotherapy and targeted immunotherapy, substantial gains have been made in the curative treatment of patients with stage 4 neuroblastoma diagnosed at over one year of age. In the last period of support, the applicant exploited three basic principles: (1) dose-intensive induction to improve remission rate and primary tumor control, (2) targeted radioimmunotherapy to eliminate occult metastatic disease, and (3) adjuvant monoclonal antibody for minimal residual disease. These evolutions in treatment strategy have produced a clear improvement in progression-free survival from 0% (N4 protocol), to 25% (N5), to 40% (N6), and now to greater than 60% for the N7 protocol. While these improved cure rates support efficacy of these novel approaches, the applicant has also applied sensitive and specific methods to measure the response of minimal residual disease. Immunofluorescence (with anti-GD2) and RT-PCR (for GAGE) have confirmed efficacy of monoclonal antibody therapy for microscopic tumors. Further, the applicant showed that a host anti-mouse response in the form of anti-idiotype (Ab2) and anti-anti-idiotype (Ab3) was associated with improved survival. Patients with positive but low Ab2 titers appeared to derive the most benefit. This application hypothesizes that the anti-idiotype network is critical for maintaining long-term remissions in these patients. To test this hypothesis directly, the applicant has produced anti-idiotypic antibodies which stimulate both B-cell and T-cell mediated anti-GD2 immune responses in mice which could protect mice from GD2-bearing B16 melanomas. GD2-oligosaccharide specificity was novel and consistent with the applicant's previous findings that T-cells could recognize carbohydrate epitopes. The unusually low optimal dosage of Ab2 paralleled clinical observations. In this application the applicant proposes to test the anti-idiotype A1G4 in a phase I clinical trial, with the intention to incorporate this vaccine modality into future protocols for neuroblastoma. The proposed studies will assess both humoral and T-cell mediated immune responses in patients following vaccination with anti-idiotypic antibody. B-lymphoblastoid lines will be transduced with retrovirus to express GD2 for T-cell studies. Immunofluorescence (new antibody panel) and RT-PCR (GAGE, MAGE, BAGE and tyrosine hydroxylase) will be used to test if minimal residual disease in blood and marrow samples will respond to immunotherapy. Based upon this phase I study, the applicant believes that the immune response to anti-idiotype vaccine can be further improved when adjuvants or engineered antigen presenting dendritic cells are optimized. Because GD2 is found on a variety of human tumors, these results may have therapeutic implications for other refractory human cancers.

描述：（申请人的摘要）使用组合化疗和 有针对性的免疫疗法，在治疗剂中取得了可观的收益 诊断为一年以上的4期神经母细胞瘤患者的治疗 年龄。 在支持的最后一个阶段，申请人利用了三个基本 原则：（1）剂量密集型诱导以提高缓解率和 原发性肿瘤控制，（2）靶向放射免疫疗法以消除隐秘 转移性疾病和（3）最小的辅助单克隆抗体 残留疾病。 这些治疗策略中的这些发展产生了 从0％（N4方案）到25％的无进展生存率明显改善 （n5），至40％（N6），而N7方案的现在大于60％。 尽管 这些提高的治愈率支持这些新方法的功效， 申请人还采用了敏感和特定的方法来测量 最小残留疾病的反应。 免疫荧光（抗GD2） RT-PCR（用于量规）已确认单克隆抗体治疗的功效 用于微观肿瘤。 此外，申请人表明主机 反小鼠反应以抗IDiotype（AB2）的形式（AB2）和 抗Anti-Idiotype（AB3）与提高的生存有关。 患者 积极但低的AB2滴度似乎是最大的好处。 这 应用假设抗IDiotype网络对于 维持这些患者的长期弥补。 检验这一假设 直接，申请人产生了抗IDiotypic抗体，该抗体 刺激小鼠中B细胞和T细胞介导的抗GD2免疫反应 可以保护小鼠免受含GD2的B16黑色素瘤。 GD2-寡糖特异性是新颖的，并且与 申请人以前的发现T细胞可以识别碳水化合物 表位。 AB2平行临床的异常低最佳剂量 观察。 在此应用程序中，申请人建议测试 在I期临床试验中，抗IDIOTYPE A1G4，目的是 将这种疫苗模态纳入神经母细胞瘤的未来方案中。 拟议的研究将评估体液和T细胞介导的免疫 抗IDiotypic抗体疫苗接种后患者的反应。 b-蛋白母细胞线将用逆转录病毒转导，以表达GD2的 T细胞研究。 免疫荧光（新抗体面板）和RT-PCR（GAGE， 法师，蝙蝠和酪氨酸羟化酶）将用于测试是否最小 血液和骨髓样品中的残留疾病将对免疫疗法有反应。 基于此阶段I研究，申请人认为免疫 佐剂或 优化了工程的抗原呈递树突状细胞。 因为GD2是 在各种人类肿瘤上发现，这些结果可能具有治疗性 对其他难治性人类癌症的影响。