Predicting toxicity and success of anti-GD2 immunotherapy of neuroblastoma

描述（由申请人提供）：神经母细胞瘤是困扰12个月以下儿童的最常见癌症，平均诊断年龄约为18个月。大约50%的患者患有高危神经母细胞瘤，尽管进行了强化化疗和自体骨髓移植，但这些儿童中有一半最终死于该病。因此，迫切需要开发新的和更有效的治疗方法。神经母细胞瘤治疗的一个重大突破涉及Yu博士开发的抗GD 2嵌合抗体ch14.18。正在进行的ch14.18 III期临床试验针对进入缓解期后诊断为高危疾病的儿童，治愈率从46%显著提高至66%。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治疗失败并死于疾病，并且存在与ch14.18治疗相关的显著毒性。因此，迫切需要鉴定新的生物标志物，其可以改善结果预测并降低毒性而不损失功效，这是本申请的焦点。我们假设可以从F受体或KIR错配的基因型预测结局，一些儿童的失败可能是由于预先存在针对ch14.18上存在的非人聚糖Neu 5Gc和α-gal残基的抗体，并且ch14.18观察到的毒性也可能是由于针对ch14.18聚糖残基的抗体，和/或由于IL-6或NO。我们将使用从儿童肿瘤组实施的两项正在进行的ch14.18临床试验中招募的患者的血液样本中采集的DNA、血浆和血清（ANBL 0032，由余博士主持，ANBL 0931），以解决以下具体目标：1）确定Fc RIIIA和Fc RIIA的基因型及其与随机接受免疫疗法的患者中ADCC活性和临床结果的相关性; 2）确定KIR和KIR配体的基因型的关联（HLA I类）与ADCC活性和随机接受免疫治疗的患者的临床结局; 3）确定血清细胞因子IL-6或血清一氧化二氮是否与ch14.18输注和治疗相关的常见毒性相关，包括过敏反应毛细血管渗漏综合征，和神经性疼痛;和4）确定血浆样品中非人聚糖Neu 5Gc和α-gal的抗体的存在和/或水平是否与对ch14.18治疗的过敏反应或结果和/或治疗后ch14.18血清水平相关。拟议的研究应该产生急需的信息，有关生物标志物，可以预测这种现已证明有效的高风险神经母细胞瘤免疫疗法的疗效和毒性。更重要的是，通过确定改善毒性、提高疗效和预测结局的方法，为治疗的“个性化”提供途径，从而提高接受治疗的儿童在最佳和最富有同情心的条件下最有可能获益的可能性，从而可能改善ch14.18治疗。

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.