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: 8868955
• 负责人: Ian F. Pollack
• 金额: $ 31.96万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868955
• 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; 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; phase II trial; 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（由申请人提供）：这项新的3年R 01申请专注于室管膜瘤（最具挑战性的儿童脑肿瘤之一）基于肽的免疫治疗的试点临床试验。虽然大约50%的肿瘤可以通过手术和放射治疗治愈，但尽管进行了后续治疗，仍有类似比例的肿瘤会复发并不可避免地进展。受影响的儿童在死于难治性肿瘤进展之前，往往会因这些干预措施而累积发病率。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，基于我们的观察，室管膜瘤经常表达高水平的特异性肿瘤相关抗原（TAAs），特别是IL 13 R2，EphA 2和生存素，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者。基于这些数据，我们建议使用TAA为基础的疫苗鸡尾酒，结合免疫佐剂（咪喹莫特），复发性室管膜瘤的儿童。因为肿瘤位置可能对有症状的免疫介导的肿瘤肿胀的可能性具有强烈的影响（即，假进展），如果存在稳健的瘤内免疫应答，则研究将合并后颅窝和非后颅窝室管膜瘤的单独分层。我们将在两个分层中的每一个中治疗总共12名患者，每3周皮下接种TAA表位疫苗，共8个疗程，联合局部咪喹莫特。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实验室提供的独特机构资源，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可以安全地治疗小儿室管膜瘤，而且还可以通过免疫学和临床参数来评估其活性。为了解决我们的假设，我们提出了以下目的的研究：1）确定TAA表位肽疫苗接种复发性室管膜瘤儿童的安全性和耐受性; 2）使用IFN-γ-酶联免疫斑点（ELISPOT）和四聚体测定法确定疫苗接种后外周血单核细胞对疫苗肽的免疫应答的速率和幅度。还将获得关于对治疗的临床和成像反应、TAA表达和反应之间的关联以及有助于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需要对这些肿瘤进行后续的更大规模的II期试验。