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期最常见和最致命的脑肿瘤之一。大多数脑干和次全切除非脑干恶性胶质瘤的儿童在诊断后几年内死亡，尽管目前的治疗。因此，需要针对这些肿瘤的独特特征的新治疗方法。在过去的十年中，我们已经获得了显着的临床前和临床经验与成人胶质瘤的免疫治疗，并建议将这些见解扩展到儿童恶性胶质瘤的治疗，基于我们的观察，这些肿瘤之间的实质相似性，在他们的胶质瘤相关抗原（GAA）的表达。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（poly-ICLC），用于新诊断的恶性脑干胶质瘤（第1层）和次全切除的非脑干恶性胶质瘤（第2层）的儿童。受试者将接受s.c.注射GAA疫苗，每3周一次，共8个疗程，并施用聚-ICLC（30 μ g/kg，i.m.）在每次接种疫苗的当天。将通过临床和实验室评价以及MR成像评价受试者的不良事件、方案限制性毒性（RLT）和治疗反应。在没有RLT的情况下表现出疾病稳定或消退的受试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，这些资源已整合到临床试验设计中。我们假设，基于疫苗的免疫治疗不仅可以安全地治疗儿童恶性胶质瘤，而且还可以通过临床、放射学和免疫学参数评估其活性。为了解决我们的假设，我们提出了以下具体目标的研究：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;和2）为了确定疫苗接种后外周血单核细胞中针对GAA肽的免疫应答的速率和幅度，使用IFN-3-酶联免疫斑点（ELISPOT）和四聚体测定，对基于肽疫苗治疗进行应答。我们将在两个分层中各治疗12例患者。还将获得关于治疗的临床和成像反应的初步数据。这项研究的结果将使我们能够确定是否有必要对其中一个或两个分层进行后续的更大规模的II期试验。 公共卫生相关性：我们的临床研究和生物相关性分析将代表基于多肽表位疫苗的策略首次应用于儿科胶质瘤队列，为评估儿科脑肿瘤背景下免疫策略的安全性以及临床和免疫学疗效提供基础数据。

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.