NOVEL COMBINATION THERAPY OF NEUROBLASTOMA

描述：(申请人摘要)使用联合化疗和 靶向免疫治疗，在治愈方面取得了实质性进展 诊断一年以上的4期神经母细胞瘤的治疗 年纪大了。在最后的支持期间，申请者利用了三个基本的 原则：(1)剂量密集诱导以提高缓解率和 初步肿瘤控制，(2)靶向放射免疫治疗以消除隐匿性 转移性疾病，以及(3)MIMAL佐剂单抗 残留病。这些治疗策略的演变产生了 无进展存活率明显提高，从0%(N4方案)提高到25% (N5)，到40%(N6)，现在到N7协议的60%以上。而当 这些提高的治愈率支持了这些新方法的有效性， 申请人还应用了敏感和具体的方法来测量 微小残留病的反应。免疫荧光(含抗GD2抗体) 和RT-PCR(用于GAGE)已经证实了单抗治疗的有效性 用于显微镜下的肿瘤。此外，申请人还表明，一名东道主 抗独特型(Ab2)和抗独特型(Ab2)形式的抗小鼠反应 抗抗独特型抗体(Ab3)与提高存活率有关。病人 具有阳性但低的AB2效价似乎获得了最大的益处。这 应用假设抗独特型网络对 维持这些患者的长期缓解。为了检验这一假说 申请人直接产生了抗独特型抗体， B细胞和T细胞同时刺激小鼠产生抗GD2免疫应答 它可以保护小鼠免受GD2-B16黑色素瘤的侵袭。 GD2-寡糖的特异性是新的，并与 申请人之前发现T细胞可以识别碳水化合物 表位。AB2的最佳剂量异常低与临床平行 观察。在本申请中，申请人提议测试 I期临床试验中的抗独特型A1G4，目的是 将这种疫苗模式纳入未来治疗神经母细胞瘤的方案中。 拟议的研究将评估体液免疫和T细胞介导的免疫 患者接种抗独特型抗体后的反应。 B淋巴母细胞系将被逆转录病毒转导表达GD2 T细胞研究。免疫荧光(新抗体组)和RT-PCR(Gage， MAGE、BAGE和酪氨酸羟化酶)将用于测试是否最小 血液和骨髓样本中的残留疾病将对免疫治疗产生反应。 基于我研究的这一阶段，申请人认为免疫 抗独特型疫苗的免疫应答可在佐剂或 优化了工程化的抗原提呈树突状细胞。因为GD2是 在各种人类肿瘤上发现的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.