IMMUNE MONITOR FOR COG TRIAL OF ANTI-GD2 IN NEUROBLASTOMA

描述（由申请人提供）： 这是一项竞争性补充拨款提案，用于继续使用由主要研究者主持的国家临床试验的标本进行临床实验室研究，该临床试验的标题为：“清髓性治疗和自体干细胞拯救后嵌合抗GD 2在高危神经母细胞瘤中的III期随机研究”。“新诊断的高危神经母细胞瘤患者将接受统一的诱导化疗，手术，然后进行自体干细胞移植（ASCT）。然后将其随机分配至13-顺式-视黄酸+/-免疫治疗组。 后者由人-小鼠嵌合抗GD 2、chl4.18和细胞因子（GM-CSF与IL-2交替）组成。 这一竞争性补充资助是由于FDA要求增加III期研究的样本量，FDA要求临床肿瘤学小组（COG）考虑如果III期研究证明了chl4.18的疗效，则可能在未来获得chl4.18的许可。 因此，对本方案进行了修订，将样本量从359例增加至423例，累积时间从3.8年增加至5年，共计8年，包括3年随访。 一般而言，抗GD 2抗体的抗肿瘤活性依赖于补体依赖性细胞毒性和抗体依赖性细胞毒性（ADCC）。 然而，ASCT后，关于中性粒细胞和淋巴细胞的ADCC能力的数据很少。 除ADCC外，由NK（CD 3-）和NK-T（CD 3+）细胞组成的CD 56+淋巴细胞被认为是响应细胞因子的免疫监视和抗肿瘤活性的主要参与者。 虽然NK细胞在移植后迅速恢复，但对NK-T细胞以及ASCT后NK活化和抑制受体的表达知之甚少。 另一个有趣的问题是FcR基因分型在ADCC活动和临床结果中的作用。 因此，沿着3期临床试验，将在特定时间点获得血液样品并运送到主要研究者的实验室用于以下特定研究：（1）连续监测由嗜中性粒细胞和单核细胞介导的ADCC活性，以确定它们在移植后环境中是否可操作以及IL-2暴露是否影响嗜中性粒细胞介导的ADCC;（2）动态监测患者外周血NK细胞、NK-T细胞、NK活性、NK活化受体和抑制受体的表达，（3）探讨免疫效应细胞数量、功能及NK受体分子表达与EFS的关系;和（4）检查FcgRlllA和FcgRllA基因型与随机接受免疫治疗的患者中ADCC活性和临床结果的相关性。 这些研究应产生重要的信息，未来的被动免疫治疗癌症的设计在设置的微小残留疾病后，单或双（串联干细胞移植）清髓性治疗。

DESCRIPTION (provided by applicant): This is a competitive supplemental grant proposal to continue the clinical-laboratory studies using specimens from a national clinical trial chaired by the principal investigator entitled: "Phase Ill Randomized Study of Chimeric antiGD2 in High Risk Neuroblastoma Following Myeloablative Therapy and Autologous Stem Cell Rescue." Newly diagnosed patients with-high risk neuroblastoma will receive uniform induction chemotherapy, surgery, followed by autologous stem cell transplantation (ASCT). They will then be randomized to 13-cis- retinoic acid +/- immunotherapy. The latter consists of a human-mouse chimeric anti-GD2, chl4.18, and cytokines (GM-CSF alternating with IL-2). This competitive supplemental grant is prompted by an increase in the sample size for the Phase 3 study in response to a request from FDA that the Clinical Oncology Group (COG) consider possible future licensure of chl4.18 should its efficacy be proven by the Phase 3 study. Accordingly, this protocol was amended to increase the sample size from 359 to 423, and accrual time from 3.8 to 5 years with a total of 8 years including 3 year follow-up. In general, the anti-tumor activities of anti-GD2 antibodies rely on complement dependent cytotoxicity and antibody dependent cellular cytotoxicity (ADCC). Following ASCT, however, there is a paucity of data regarding the ADCC capabilities of neutrophils and lymphocytes. In addition to ADCC, CD56+ lymphocytes which consist of NK (CD3-) and NK-T (CD3+) cells are believed to be major players in immune surveillance and antitumor activities in response to cytokines. Although NK was said to recover rapidly after transplant, little is known about NK-T cells and the expression of NK activation and inhibitory receptors post-ASCT. Another intriguing issue is the role of FcR genotyping in ADCC activities and clinical outcome. Thus, along with the Phase 3 clinical trials, blood samples will be obtained at specified time points and shipped to the principal investigator's lab for the following specific studies: (1) serial monitoring of ADCC activities mediated by neutrophils and mononuclear cells to determine whether they are operational in the post-transplant setting and whether IL-2 exposure affects neutrophil mediated ADCC; (2) serial monitoring of number of NK cells, NK-T cells, NK activity, and expression of NK activation and inhibitory receptors; (3) exploring the relationship between immune effector cell number, functions and expression of NK receptor molecules with EFS in patients; and (4) examining the correlation of the genotypes of FcgRlllA and FcgRllA with ADCC activity and clinical outcome in patients randomized to immunotherapy. These studies should yield important information crucial to the design of future passive immunotherapy of cancer in the setting of minimal residual disease following single or double (tandem stem transplantation) myeloablative therapy.