Peptide-Based Vaccine Therapy for Childhood Malignant Gliomas

儿童恶性胶质瘤的肽疫苗治疗

• 批准号: 8020082
• 负责人: Hideho Okada
• 金额: $ 30.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020082
• 关键词: Address; Adult Glioma; Adverse event; Affect; Anaplastic astrocytoma; Antigens; Biological; Biological Assay; Brain Stem; Brain Stem Glioma; Child; Childhood; Childhood Brain Neoplasm; Childhood Glioma; Clinical; Clinical Research; Clinical Trials Design; Clinical/Radiologic; Cytotoxic Chemotherapy; Cytotoxic T-Lymphocytes; Data; Diagnosis; Disease; Enzymes; Epitopes; Evaluation; Foundations; Future; Glioma; Image; Immune response; Immunologic Adjuvants; Immunologic Monitoring; Immunologics; Immunotherapeutic agent; Immunotherapy; Injection of therapeutic agent; Interferons; Intramuscular; Laboratories; Link; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Glioma; Newly Diagnosed; Participant; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phase II Clinical Trials; Poly ICLC; Progression-Free Survivals; Radiation; Regimen; Resected; Resources; Safety; Spottings; Survival Rate; T-Lymphocyte Epitopes; Therapy Clinical Trials; Toxic effect; Vaccination; Vaccine Antigen; Vaccine Therapy; Vaccines; base; chemotherapy; cohort; experience; improved; insight; irradiation; peptide based vaccine; pre-clinical; public health relevance; response; temozolomide; treatment response; tumor

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.

描述（由申请人提供）：恶性星形胶质细胞瘤是儿童期最常见和致命的脑肿瘤之一。大多数患有脑干和小计切除的非脑系统恶性神经胶质瘤的儿童在诊断后的几年内死亡，尽管目前治疗。因此，需要采用新的治疗方法来瞄准这些肿瘤的独特特征。在过去的十年中，基于我们观察到这些肿瘤在神经胶质瘤相关的抗原（GAAS）表达的实质性相似性的基础上，我们在成人神经膜瘤的免疫疗法方面获得了显着的临床前和临床经验，并提议将这些见解扩展到对儿童恶性神经胶质瘤的治疗。在这些数据的基础上，我们建议使用新诊断为新诊断的恶性脑干神经胶质瘤（地层1）的儿童和非脑部切除的非脑干系统恶性肿瘤（Stratum 2），建议使用基于GAA的疫苗鸡尾酒（Poly-ICLC）结合使用免疫助理（Poly-ICLC）。参与者将接受S.C.每次疫苗接种当天，每3周注射一次GAA疫苗每3周进行8疗程和聚-ICLC的注射（30 <g/kg I.M.）。将通过临床和实验室评估和MR成像评估参与者的不良事件，方案限制毒性（RLT）以及治疗反应。没有RLT的疾病稳定或消退的参与者可能会接受其他疫苗接种。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，这些资源已融入临床试验设计中。我们假设基于疫苗的免疫疗法不仅可以证明可用于治疗小儿恶性神经胶质瘤，而且还将证明通过临床，放射学和免疫学参数评估的活性。为了解决我们的假设，我们提出了以下具体目的的研究：1）使用多个与神经胶质瘤相关的抗原肽和免疫辅助治疗评估疫苗接种的安全性，并在具有新诊断的脑干并进行了亚计分解的非脑干系统高度高级Gliomas的儿童中； 2）使用IFN-3-酶 - 酶 - 连接的免疫点（ELISPOT）和Tetramer分析，为了确定疫子后血液单核细胞对GAA肽的免疫反应的速率和大小。我们将在两个阶层中的每个阶层中总共处理12例患者。还将获得有关临床和成像反应对治疗的初步数据。这项研究的结果将使我们能够确定对随后的II期较大阶段试验是否应为两层或两个层。 公共卫生相关性：我们的临床研究和生物学相关性分析将代表基于多肽表位疫苗策略在儿科胶质瘤队列中的首次应用，提供了评估安全性和免疫学功效的基本数据，以及在儿科脑肿瘤上的免疫治疗策略。

项目成果

Increased expression of tumor-associated antigens in pediatric and adult ependymomas: implication for vaccine therapy.

• DOI: 10.1007/s11060-012-0998-x
• 发表时间: 2013-01
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: Yeung, Jacky T.;Hamilton, Ronald L.;Okada, Hideho;Jakacki, Regina I.;Pollack, Ian F.
• 通讯作者: Pollack, Ian F.