NOVEL COMBINATION THERAPY OF NEUROBLASTOMA

描述：（申请人的摘要）使用联合化疗和 靶向免疫疗法，在治疗方面取得了实质性进展， 治疗在一年以上诊断为4期神经母细胞瘤的患者 年龄。 在上一个支持期内，申请人利用了三个基本的 原则：（1）剂量强化诱导，提高缓解率， 原发性肿瘤控制，（2）靶向放射免疫治疗，以消除隐匿性 转移性疾病，和（3）辅助单克隆抗体，用于最小 残留病 这些治疗策略的演变产生了一个 无进展生存期从0%（N4方案）明显改善至25% (N5)40%（N6），现在对于N7协议大于60%。 而 这些提高的治愈率支持了这些新方法的功效， 申请人还应用了敏感且特定的方法来测量 微小残留病的反应。 免疫荧光（使用抗GD 2） 和RT-PCR（用于GAGE）已证实单克隆抗体治疗的有效性 显微镜下的肿瘤 此外，申请人表明， 抗独特型（Ab 2）形式的抗小鼠应答， 抗-抗-独特型抗体（Ab 3）与存活率的提高相关。 患者 具有阳性但低Ab 2滴度的小鼠似乎获得最大益处。 这 应用程序假设抗独特型网络对于 维持这些患者的长期缓解。 为了验证这一假设 申请人直接生产了抗独特型抗体， 在小鼠中刺激B细胞和T细胞介导抗GD 2免疫应答 它可以保护小鼠免受携带GD 2的B16黑色素瘤的侵害。 GD 2-寡糖特异性是新的，与 申请人先前发现T细胞可以识别碳水化合物 表位 异常低的Ab 2最佳剂量使临床 意见。 在本申请中，申请人提出测试 I期临床试验中的抗独特型A1 G4，目的是 将这种疫苗模式纳入未来的神经母细胞瘤治疗方案。 拟议的研究将评估体液和T细胞介导的免疫 患者接种抗独特型抗体后的反应。 B淋巴母细胞系将用逆转录病毒转导以表达GD 2， T细胞研究。 免疫荧光（新抗体组）和RT-PCR（GAGE， 法师、巴格和酪氨酸羟化酶）将用于检测 血液和骨髓样品中的残留疾病将对免疫疗法产生反应。 基于该I期研究，申请人认为免疫 当使用佐剂或 优化工程化的抗原呈递树突细胞。 因为GD 2是 在各种人类肿瘤中发现，这些结果可能具有治疗作用。 对其他难治性人类癌症的影响。

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.