IMMUNE MONITOR FOR COG TRIAL OF ANTI-GD2 IN NEUROBLASTOMA

神经母细胞瘤中抗 GD2 抗体 COG 试验的免疫监测

• 批准号: 7630451
• 负责人: Alice L. Yu
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7630451
• 关键词: IMMUNE; MONITOR; COG; TRIAL; ANTI

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.

描述（由申请人提供）： 这是一项具有竞争性的补充赠款提案，旨在使用由主要研究者主持的国家临床试验的标本继续进行临床实验室研究，该试验题为：“偶然的嵌合抗原阶段不随机研究在脊髓损伤治疗后高风险神经母细胞瘤中进行的嵌合抗原和自体干细胞救援。” 新诊断的患有高风险神经细胞瘤的患者将接受均匀的诱导化疗，手术，然后进行自体干细胞移植（ASCT）。然后，它们将被随机分为13-秒视网膜酸+/-免疫疗法。 后者由人鼠嵌合抗GD2，CHL4.18和细胞因子（GM-CSF与IL-2交替）组成。 这种竞争性补充赠款是由于第三阶段研究的样本量增加而引起的，这是对FDA的要求，即临床肿瘤学组（COG）考虑了CHL4.18的未来许可，应通过第3阶段研究证明其疗效。 因此，对该方案进行了修改，以将样本量从359增加到423个，并从3.8年增加到5年，总计8年，包括3年随访。 通常，抗GD2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细胞毒性（ADCC）。 但是，在ASCT之后，关于中性粒细胞和淋巴细胞的ADCC能力的数据很少。 除ADCC外，CD56+由NK（CD3-）和NK-T（CD3+）细胞组成的CD56+淋巴细胞被认为是免疫监测和抗肿瘤活性的主要参与者。 尽管据说NK在移植后迅速恢复，但对NK-T细胞以及NK激活和抑制性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，与第三阶段的临床试验一起，将在指定的时间点获得血样，并运往首席研究员实验室进行以下具体研究：（1）对中性粒细胞和单核细胞介导的ADCC活性的串行监测，以确定它们是否在后植物环境中起作用，并在后植物的环境和IL-2暴露中是否在IL-2 exposeal中进行中性粒细胞中性ADCC; （2）对NK细胞数量，NK-T细胞，NK活性以及NK激活和抑制受体表达的序列监测； （3）探索患者中EFS的免疫效应细胞数，NK受体分子的功能和表达之间的关系； （4）检查随机对免疫疗法的患者，FCGRLLLA和FCGRLLA的基因型与ADCC活性和临床结果的相关性。 这些研究应产生对未来的被动免疫疗法设计至关重要的重要信息，从而在单次或双重（串联茎移植）骨髓性疗法后最少残留疾病。