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）：神经母细胞瘤是最常见的癌症，遭受了十二个月以下的儿童，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屈服于该疾病。因此，有一种迫切需要开发新的，更有效的疗法。神经母细胞瘤治疗的一个主要突破涉及Yu博士的抗GD2嵌合抗体CH14.18的发展。 CH14.18的III期临床试验的临床试验针对被诊断出患有高危疾病后的儿童，已导致治愈率从46％升至66％。但是，尽管有这一突破，但仍然很明显，几乎三分之一的儿童继续失败并屈服于该疾病，并且与CH14.18治疗有关。因此，迫切需要鉴定新的生物标记物，这些标志物可以完善结果预测并降低毒性而不会丧失疗效，这是本应用的重点。我们假设可以通过F受体或KIR失配的基因型预测结果，某些儿童的失败可能是由于针对非人类Glycans neu5gc和α-GAL残留物的抗体存在，这些抗体存在于CH14.14上，以及与CH14的毒性相关的CH14.14.14.14.14.14。和/或归因于IL-6或否。我们将使用从儿童肿瘤学组实施的两项正在进行的CH14.18临床试验的患者的血液样本中采集的DNA，血浆和血清（ANBL0032，由YU博士主持，ANBL0931和ANBL0931），以解决以下具体目的：1：1）确定临床和FC RIIIA和FC RIIIA和FC RIIIA和FC RIIIA和FC RIIIA的基因型）。免疫疗法； 2）确定KIR和KIR配体（HLA I类）基因型与随机进行免疫疗法的患者的ADCC活性和临床结果的关联； 3）确定血清细胞因子IL-6或血清一氧化二氮是否与与CH14.18输注和治疗相关的常见毒性有关，包括超敏反应毛细血管泄漏综合征和神经性疼痛； 4）确定血浆样品中非人类聚糖Neu5GC和α-GAL的抗体的存在和/或水平是否与CH14.18治疗和/或治疗后CH14.18血清水平有关。拟议的研究应产生有关生物标志物的急需信息，这些信息可能可以预测该现象的高风险神经母细胞瘤的有效免疫疗法的功效和毒性。更重要的是，通过确定改善毒性，提高治疗功效并预测结果的方法来增加治疗的“个性化”途径，从而提高了治疗方法的“个性化”，从而提高了治疗方法，从而增加了治疗的可能性，从而增加了治疗的可能性是最佳和富有同情心的儿童受益最佳。