Peptide vaccine-based immunotherapy for children with recurrent ependymomas.

基于肽疫苗的免疫疗法治疗复发性室管膜瘤儿童。

• 批准号: 8478400
• 负责人: Ian F. Pollack
• 金额: $ 31.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-06 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478400
• 关键词: Address; Adult; Adverse event; Affect; Astrocytoma; Biological; Biological Assay; Brain Neoplasms; Brain Stem; Cancer Vaccines; Child; Childhood Astrocytic Tumor; Childhood Brain Neoplasm; Childhood Ependymoma; Clinical; Clinical Research; Clinical Trials; Coupled; Cytotoxic T-Lymphocytes; Data; Disease; Enzymes; Ependymoma; Epitopes; Evaluation; Fossa; Gene Expression; Image; Imiquimod; Immune; Immune Response Genes; Immune Targeting; Immune response; Immunity; Immunologic Adjuvants; Immunologic Monitoring; Immunologics; Immunotherapeutic agent; Immunotherapy; Interferons; Intervention; Laboratories; Link; Location; Magnetic Resonance Imaging; Mediating; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Participant; Patients; Peptide Vaccines; Peptides; Peripheral Blood Mononuclear Cell; Phase II Clinical Trials; Pilot Projects; Posterior Fossa; Proteins; Recurrence; Refractory; Regimen; Resistance; Resources; Safety; Series; Severities; Spottings; Structure; Swelling; T-Lymphocyte Epitopes; Time; Toxic effect; Tumor Antigens; Vaccination; Vaccine Antigen; Vaccine Therapy; Vaccines; base; chemotherapy; cohort; design; experience; immunoreactivity; innovation; insight; irradiation; novel; peptide based vaccine; pre-clinical; protein expression; public health relevance; response; subcutaneous; survivin; treatment response; tumor; tumor progression; vaccine efficacy

DESCRIPTION (provided by applicant): This novel 3-year R01 application focuses on a pilot clinical trial of peptide-based immunotherapy for ependymomas, among the most challenging childhood brain tumors. Although approximately 50% of tumors are cured with surgery and irradiation, a similar percentage of tumors recur and progress inexorably despite subsequent therapies. Affected children often experience cumulative morbidity from these interventions, before succumbing to refractory tumor progression. 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 and pediatric astrocytomas, and propose to extend these insights to the treatment of childhood ependymomas, based on our observation that ependymomas frequently express high levels of specific tumor-associated antigens (TAAs), particularly IL13R¿2, EphA2, and survivin, often far exceeding levels we have observed in astrocytic tumors, which suggests that these tumors may be exceptionally promising candidates for immunotherapy. Building upon these data, we propose the use of a TAA-based vaccine cocktail, combined with an immunoadjuvant (imiquimod), for children with recurrent ependymomas. Because tumor location may have a strong impact on the potential for symptomatic immune- mediated tumor swelling (i.e., pseudoprogression), if there is a robust intratumoral immune response, the study will incorporate separate strata for posterior fossa and non-posterior fossa ependymomas. We will treat a total of 12 patients in each of the two strata with subcutaneous TAA epitope vaccinations every 3 weeks for 8 courses combined with topical imiquimod. 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 receive additional vaccinations. These studies take advantage of unique institutional resources provided by our Immunologic Monitoring Laboratory, which are integrated into the clinical trial. We hypothesize that vaccine-based immunotherapy will not only prove safe for the treatment of pediatric ependymomas, but will also demonstrate activity as assessed by immunologic and clinical parameters. To address our hypotheses, we propose studies with the following aims: 1) To determine safety and tolerability of vaccination with TAA epitope peptides for children with recurrent ependymomas; and 2) To define the rate and magnitude of immune response in post-vaccine peripheral blood mononuclear cells against vaccine peptides, using IFN-¿-enzyme-linked immuno-spot (ELISPOT) and tetramer assays. Preliminary data will also be obtained regarding clinical and imaging responses to therapy, associations between TAA expression and response, and mechanisms contributing to tumor resistance to immunotherapy. The results from this study, which would be the first vaccine-based trial conducted for ependymomas, will allow us to determine whether a subsequent larger phase II trial is warranted for these tumors.

描述(申请人提供)：这一新的为期3年的R01申请专注于室管膜瘤的基于多肽的免疫治疗的试点临床试验，室管膜瘤是最具挑战性的儿童脑瘤之一。虽然大约50%的肿瘤通过手术和放射治疗得以治愈，但尽管随后进行了治疗，也有类似比例的肿瘤复发和进展。受影响的儿童在死于难治性肿瘤进展之前，通常会经历这些干预措施的累积发病率。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，我们在成人和儿童星形细胞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室管膜瘤的治疗，因为我们观察到室管膜瘤经常表达高水平的特定肿瘤相关抗原(TAA)，特别是IL13R[2]、EphA2和Survivin，通常远远超过我们在星形细胞肿瘤中观察到的水平，这表明这些肿瘤可能是非常有希望的免疫治疗候选对象。基于这些数据，我们建议使用基于TAA的疫苗鸡尾酒，结合免疫佐剂(咪喹莫特)，用于复发性室管膜瘤的儿童。由于肿瘤的位置可能对症状性免疫介导的肿瘤肿胀(即假性进展)的可能性有很大的影响，如果有强大的肿瘤内免疫反应，该研究将包括后颅窝和非后颅窝室管膜瘤的不同层面。两层共12例，每3周皮下接种一次TAA表位疫苗，联合外用咪喹莫特8个疗程。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而表现出疾病稳定或消退的参与者可能会接受额外的疫苗接种。这些研究利用了我们的免疫监测实验室提供的独特的机构资源，这些资源被整合到临床试验中。我们假设，基于疫苗的免疫治疗不仅被证明对儿科室管膜瘤的治疗是安全的，而且根据免疫学和临床参数的评估，也将显示出活性。为了解决我们的假设，我们建议进行以下研究：1)确定复发性室管膜瘤儿童接种TAA表位多肽的安全性和耐受性；2)使用干扰素-β-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疫苗多肽的免疫反应率和大小。还将获得有关治疗的临床和影像反应、TAA表达和反应之间的关联以及导致肿瘤对免疫治疗耐药的机制的初步数据。这项研究的结果将是第一个针对室管膜瘤进行的基于疫苗的试验，将使我们能够确定是否有必要对这些肿瘤进行后续的更大规模的II期试验。