Predicting toxicity and success of anti-GD2 immunotherapy of neuroblastoma

预测神经母细胞瘤抗 GD2 免疫治疗的毒性和成功率

• 批准号: 8636909
• 负责人: Alice L. Yu
• 金额: $ 31.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636909
• 关键词: Address; Adverse effects; Affect; Aftercare; Age; Age-Months; Allergic Reaction; Antibodies; Autologous Bone Marrow Transplantation; Biological Markers; Blood Pressure; Blood specimen; Capillary Leak Syndrome; Child; Children' s Oncology Group; Clinical; Clinical Trials; DNA; Development; Diagnosis; Disease; Disease remission; Drops; Enrollment; Failure; Fc Receptor; Future; Genotype; Granulocyte-Macrophage Colony-Stimulating Factor; Hypersensitivity; Immune response; Immunotherapy; Infusion procedures; Interleukin-2; Interleukin-6; Isotretinoin; Lead; Left; Ligands; Light; London; Malignant Neoplasms; Membrane Proteins; Modality; Monoclonal Antibody Ch14.18; Neuroblastoma; Nitrous Oxide; Outcome; Pain; Pathway interactions; Patients; Pharmacologic Substance; Phase III Clinical Trials; Plasma; Polysaccharides; Randomized; Rare Diseases; Reaction; Regimen; Relapse; Reporting; Research; Sampling; Serum; Therapeutic; Toxic effect; Treatment Efficacy; United States; allergic response; antibody-dependent cell cytotoxicity; chemotherapy; chimeric antibody; cytokine; effective therapy; high risk; improved; neuroblastoma cell; painful neuropathy; receptor; success; tumor

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.

描述（由申请人提供）：神经母细胞瘤是十二个月以下儿童最常见的癌症，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，但其中一半的儿童最终还是死于这种疾病。因此，迫切需要开发新的、更有效的疗法。神经母细胞瘤治疗的一项重大突破涉及由Yu博士开发的抗GD2嵌合抗体ch14.18。正在进行的 ch14.18 III 期临床试验针对的是进入缓解期后诊断为高危疾病的儿童，已使治愈率从 46% 显着提高至 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治疗失败并死于该疾病，并且 ch14.18 治疗存在显着的毒性。因此，迫切需要鉴定新的生物标记物，这些标记物可以改进结果预测并降低毒性而不丧失疗效，这是本应用的重点。我们假设结果可以通过 F 受体或 KIR 不匹配的基因型来预测，一些儿童的失败可能是由于预先存在针对 ch14.18 上存在的非人类聚糖 Neu5Gc 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学组（ANBL0032，由 Yu 博士主持）和 ANBL0931 主持的两项正在进行的 ch14.18 临床试验中采集的患者血液样本中采集的 DNA、血浆和血清来实现以下具体目标：1 ) 确定 Fc RIIIA 和 Fc RIIA 的基因型及其与随机接受免疫治疗的患者 ADCC 活性和临床结果的相关性； 2) 确定 KIR 和 KIR 配体（HLA I 类）的基因型与随机接受免疫治疗的患者的 ADCC 活性和临床结果之间的关联； 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有关，包括过敏反应、毛细血管渗漏综合征和神经性疼痛； 4) 确定血浆样品中非人聚糖 Neu5Gc 和 α-gal 抗体的存在和/或水平是否与 ch14.18 治疗和/或治疗后 ch14.18 血清的过敏反应或结果相关水平。拟议的研究应该会产生有关生物标志物的急需信息，这些信息可以预测这种现已被证明有效的高风险神经母细胞瘤免疫疗法的功效和毒性。更重要的是，它可能通过确定改善毒性、提高治疗效果和预测结果的方法，为治疗的“个性化”提供一条途径，从而改善 ch14.18 治疗，从而增加接受治疗的儿童的可能性。儿童最有可能在最理想和富有同情心的条件下受益。

项目成果

Chimeric antibody c.8B6 to O-acetyl-GD2 mediates the same efficient anti-neuroblastoma effects as therapeutic ch14.18 antibody to GD2 without antibody induced allodynia.

针对 O-乙酰基-GD2 的嵌合抗体 c.8B6 介导与针对 GD2 的治疗性 ch14.18 抗体相同的有效抗神经母细胞瘤作用，而没有抗体诱导的异常性疼痛。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Terme, Mickaël;Dorvillius, Mylène;Cochonneau, Denis;Chaumette, Tanguy;Xiao, Wenhua;Diccianni, Mitchell B;Barbet, Jacques;Yu, Alice L;Paris, François;Sorkin, Linda S;Birklé, Stéphane
• 通讯作者: Birklé, Stéphane