Peptide-Based Vaccine Therapy for Childhood Malignant Gliomas

描述(申请人提供)：恶性星形细胞瘤是儿童最常见和最致命的脑肿瘤之一。大多数患有脑干和次全切除非脑干恶性胶质瘤的儿童在确诊后几年内死亡，尽管目前有治疗方法。因此，需要针对这些肿瘤的独特特征的新的治疗方法。在过去的十年中，我们在成人胶质瘤的免疫治疗方面获得了重要的临床前和临床经验，并建议将这些见解扩展到儿童恶性胶质瘤的治疗，基于我们观察到这些肿瘤在表达胶质瘤相关抗原(CAS)方面的本质相似之处。在这些数据的基础上，我们建议使用基于GAA的疫苗鸡尾酒，结合免疫佐剂(PolyICLC)，用于新诊断的恶性脑干胶质瘤(层1)和次全切除的非脑干恶性胶质瘤(层2)的儿童。参与者将接受S.C.的治疗。每3周注射一次GAA疫苗，共8个疗程，并将给予Poly-ICLC(30&lt；g/kg肌肉注射)。在每次接种疫苗的当天。参与者将通过临床和实验室评估以及磁共振成像来评估不良事件、方案限制毒性(RLT)和治疗反应。没有RLT表现出疾病稳定或消退的参与者可以接受额外的疫苗接种。这些研究利用了我们的免疫监测和细胞产品实验室提供的独特机构资源，这些资源被整合到临床试验设计中。我们假设，疫苗免疫疗法不仅对儿童恶性胶质瘤的治疗是安全的，而且根据临床、放射学和免疫学参数的评估，也将显示出活性。为了解决我们的假设，我们提出了以下特定目标的研究：1)评估在新诊断的脑干和次全切除的非脑干高级别胶质瘤儿童中使用多种胶质瘤相关抗原肽的疫苗接种和免疫辅助治疗的安全性；以及2)使用干扰素-3-酶联免疫斑点(ELISPOT)和四聚体分析，确定疫苗接种后外周血单个核细胞对GAA多肽的免疫反应率和免疫反应量。我们将在这两个层面分别治疗总共12名患者。还将获得有关治疗的临床和影像反应的初步数据。这项研究的结果将使我们能够确定是否需要对其中一层或两层进行后续更大规模的II期试验。 公共卫生相关性：我们的临床研究和生物学相关性分析将首次将基于多肽表位疫苗的策略应用于儿童脑胶质瘤队列，为评估儿童脑瘤免疫治疗策略的安全性以及临床和免疫学效果提供基础数据。

DESCRIPTION (provided by applicant): Malignant astrocytomas are among the most common and deadly brain tumors of childhood. Most children with brainstem and subtotally resected non-brainstem malignant gliomas die within several years of diagnosis, despite current treatments. Accordingly, new treatment approaches are needed that target the unique features of these tumors. During the last decade, we have gained significant preclinical and clinical experience with immunotherapy for adult gliomas, and propose to extend these insights to the treatment of childhood malignant gliomas, based on our observation of substantial similarities between these tumors in their expression of glioma-associated antigens (GAAs). Building upon these data, we propose the use of a GAA- based vaccine cocktail, combined with an immunoadjuvant (poly-ICLC), for children with newly diagnosed malignant brainstem gliomas (Stratum 1) and subtotally resected non-brainstem malignant gliomas (Stratum 2). Participants will be treated with s.c. injections of GAA vaccines every 3 weeks for 8 courses and poly-ICLC will be administered (30 <g/kg i.m.) on the day of each vaccination. Participants will be evaluated for adverse events, regimen limiting toxicity (RLT), and treatment response by clinical and laboratory evaluations and MR imaging. Participants who demonstrate disease stabilization or regression without RLT may undergo additional vaccinations. These studies take advantage of unique institutional resources provided by our Immunological Monitoring and Cellular Products Laboratory, which are integrated into the clinical trial design. We hypothesize that vaccine-based immunotherapy will not only prove safe for the treatment of pediatric malignant gliomas, but will also demonstrate activity as assessed by clinical, radiologic, and immunologic parameters. To address our hypotheses, we propose studies with the following specific aims: 1) To assess safety of vaccination using multiple glioma-associated antigen peptides and immunoadjuvant therapy in children with newly diagnosed brainstem and subtotally resected non-brainstem high-grade gliomas; and 2) To determine the rate and magnitude of immune response in post-vaccine peripheral blood mononuclear cells against GAA peptides, in response to peptide-based vaccine therapy, using IFN-3-enzyme-linked immuno-spot (ELISPOT) and tetramer assays. We will treat a total of 12 patients in each of the two strata. Preliminary data regarding clinical and imaging responses to therapy will also be obtained. The results from this study will allow us to determine whether a subsequent larger, phase II trial is warranted for either or both strata. PUBLIC HEALTH RELEVANCE: Our clinical study and biological correlative analyses will represent the first application of a multipeptide epitope vaccine-based strategy to a pediatric glioma cohort, providing fundamental data for assessing safety, and clinical and immunological efficacy, of immunotherapeutic strategies in the pediatric brain tumor context.