IMMUNE MONITOR FOR COG TRIAL OF ANTI-GD2 IN NEUROBLASTOMA

神经母细胞瘤中抗 GD2 抗体 COG 试验的免疫监测仪

• 批准号: 7392375
• 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/7392375
• 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）： 这是一项竞争性补充拨款提案，旨在使用主要研究者主持的一项国家临床试验的标本继续进行临床实验室研究，题为“清髓治疗和自体干细胞救援后高风险神经母细胞瘤嵌合抗GD2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）。然后他们将被随机分配接受 13-顺-视黄酸 +/- 免疫治疗。 后者由人-小鼠嵌合抗 GD2、chl4.18 和细胞因子（GM-CSF 与 IL-2 交替）组成。 这项竞争性补充拨款是由于 3 期研究样本量的增加而引起的，这是为了响应 FDA 的要求，即临床肿瘤学组 (COG) 考虑未来可能对 chl4.18 进行许可，如果其功效得到 3 期研究的证实学习。 因此，对该方案进行了修改，将样本量从 359 个增加到 423 个，累积时间从 3.8 年增加到 5 年，总共 8 年，包括 3 年随访。 一般来说，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。 除了 ADCC 之外，由 NK (CD3-) 和 NK-T (CD3+) 细胞组成的 CD56+ 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。 尽管据说 NK 移植后会迅速恢复，但人们对 ASCT 后 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，随着3期临床试验的进行，将在指定的时间点采集血液样本，并运送到主要研究者的实验室进行以下具体研究：（1）连续监测中性粒细胞和单核细胞介导的ADCC活动，以确定它们是否在移植后环境中是否有效以及 IL-2 暴露是否影响中性粒细胞介导的 ADCC； (2)连续监测NK细胞数量、NK-T细胞、NK活性以及NK激活和抑制受体的表达； (3)探讨患者免疫效应细胞数量、功能及NK受体分子表达与EFS的关系； (4)检查FcgRIIIA和FcgRllA的基因型与随机接受免疫治疗的患者的ADCC活性和临床结果的相关性。 这些研究应该产生重要信息，对于设计未来在单次或双次（串联干移植）清髓治疗后的微小残留病情况下的癌症被动免疫治疗至关重要。