Predicting toxicity and success of anti-GD2 immunotherapy of neuroblastoma

描述(申请人提供)：神经母细胞瘤是最常见的癌症，困扰12个月以下的儿童，平均确诊年龄约18个月。大约50%的患者患有高危神经母细胞瘤，其中一半儿童最终死于这种疾病，尽管进行了密集的化疗和自体骨髓移植。正因为如此，迫切需要开发新的、更有效的治疗方法。神经母细胞瘤治疗方面的一项重大突破涉及Yu博士开发的抗GD2嵌合抗体ch14.18。正在进行的ch14.18第三阶段临床试验针对的是被诊断患有高危疾病的儿童，他们进入缓解期后，治愈率从46%显著提高到66%。然而，尽管取得了这一突破，但仍然清楚的是，近三分之一的儿童继续未能通过治疗并死于这种疾病，而且与ch14.18治疗相关的毒性很大。因此，迫切需要鉴定新的生物标志物，以改进结果预测并在不损失疗效的情况下减少毒性，这是本应用的重点。我们假设，结果可以通过F受体或KIR错配的基因类型来预测，一些儿童的失败可能是由于先前存在的针对ch14.18上存在的非人类糖链Neu5Gc和α-半乳糖残基的抗体，以及ch14.18观察到的毒性也可能是由于针对ch14.18的糖链残基的抗体，和/或由于IL-6或NO。我们将使用儿童肿瘤学小组正在进行的两项ch14.18临床试验(由Yu博士担任主席的ANBL0032和ANBL0931)患者的血液样本中的DNA、血浆和血清来解决以下具体目标：1)在随机接受免疫治疗的患者中，确定Fc RIIIA和Fc RIIA基因及其与ADCC活动和临床结果的相关性；2)确定KIR和KIR配体(HLAI类)基因与随机接受免疫治疗患者的ADCC活动和临床结果的相关性；3)确定血清细胞因子IL-6或血清一氧化二氮是否与注射和治疗ch14.18相关的常见毒性有关，包括超敏反应毛细血管渗漏综合征和神经病理性疼痛；以及4)确定血浆样本中抗非人类糖链Neu5Gc和α-Gal抗体的存在和/或水平是否与ch14.18治疗的过敏反应或结果和/或治疗后ch14.18血清水平有关。这项拟议的研究应该会产生关于生物标志物的迫切需要的信息，这些信息可以预测这种现已被证明有效的高危神经母细胞瘤免疫疗法的疗效和毒性。更重要的是，它可能导致CH14.18治疗的改进，通过确定减轻毒性、提高治疗效果和预测结果的方法，为“个性化”治疗提供一条途径，从而增加接受治疗的儿童在最理想和富有同情心的条件下最有可能受益的可能性。

DESCRIPTION (provided by applicant): Neuroblastoma is the most common cancer afflicting children under twelve months of age with average age of diagnosis about 18 months. Approximately 50% of patients have high-risk neuroblastoma, with half of these children eventually succumbing to the disease despite intensive chemotherapy and autologous bone marrow transplantation. Because of this, there is an urgency to develop new and more effective therapies. One major breakthrough in neuroblastoma treatment has involved the development of the anti-GD2 chimeric antibody ch14.18 by Dr. Yu. Ongoing phase III clinical trials of ch14.18, targeted to children diagnosed with high-risk disease after they enter remission, have resulted in a significant improvement in cure rate from 46% to 66%. Despite this breakthrough, however, it is still clear that almost one-third of the children continue to fail therapy and succumb to the disease, and there are significant toxicities associated with ch14.18 therapy. Thus, there is a pressing need for the identification of new biological markers that can refine outcome prediction and decrease toxicities without loss of efficacy, which is the focus of this application. We hypothesize that outcome may be predicted from the genotypes of the F receptor or KIR mismatch, that failure in some children may be due to preexisting antibodies against the non-human glycans Neu5Gc and alpha-gal residues which are present on ch14.18, and that the toxicities observed with ch14.18 may also be due to antibodies against the glycan residue of ch14.18, and/or be due to IL-6 or NO. We will use DNA, plasma and serum taken from blood samples of patients enrolled in two ongoing clinical trials of ch14.18 implemented by the Children's Oncology Group (ANBL0032, chaired by Dr. Yu, and ANBL0931) to address the following specific aims: 1) Determine the genotypes of Fc RIIIA and Fc RIIA and their correlation with ADCC activity and clinical outcome in patients randomized to immunotherapy; 2) Determine the association of genotypes for KIR and KIR ligands (HLA class I) with ADCC activity and clinical outcome in patients randomized to immunotherapy; 3) Determine if the serum cytokine IL-6 or serum nitrous oxide is associated with common toxicities associated with ch14.18 infusion and treatment, including hypersensitivity reaction capillary leak syndrome, and neuropathic pain; and 4) Determine if the presence and/or levels of antibodies to the non-human glycans Neu5Gc and alpha-gal in plasma samples is associated with allergic response or outcome to ch14.18 therapy, and/or post-treatment ch14.18 serum levels. The proposed research should yield the much needed information regarding biomarkers that may predict efficacy and toxicities of this now proven effective immunotherapy of high risk neuroblastoma. More importantly, it may lead to an improvement in ch14.18 therapy by providing a pathway for the "personalization" of treatment by identifying ways to ameliorate toxicities, increase therapeutic efficacy, and predict outcome, thereby increasing the likelihood the child being treated is a child most likely to benefit under the most optimal and compassionate conditions.