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（由应用程序提供）：这种新型的3年R01应用集中在基于肽的免疫疗法的试验临床试验上，这是儿童脑肿瘤最挑战的最挑战的。尽管大约50％的肿瘤通过手术和辐照治愈，但相似的肿瘤复发和进展比例可以不可避免地成功随后的疗法。受影响的儿童在屈服于难治性肿瘤进展之前，经常从这些干预措施中经历累积发病率。 According to the last decade, we have gained significant preclinical and clinical experience with immunotherapy for adult and pediatric astrocytomas, and proposal 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在星形胶质性肿瘤中，这表明这些肿瘤可能异常承诺候选免疫疗法。在这些数据的基础上，我们建议将基于TAA的疫苗鸡尾酒与免疫辅助（imiquimod）结合使用，用于复发性转化症的儿童。由于肿瘤的位置可能对症状免疫介导的肿瘤吞咽的潜力有很大的影响（即，假孕），如果存在强大的肿瘤内免疫反应，则该研究将融合后孔后孔和非降低肌脱甲虫的分层。我们将在两个层中的每个阶层中总共进行12例患者，每3周，皮下TAA表位接种疫苗与局部咪喹莫原这样的8个疗程相结合。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实验室提供的独特机构资源，这些资源已整合到临床试验中。我们假设基于疫苗的免疫疗法不仅可以证明对儿科室心症的治疗安全，而且还将证明通过免疫和临床参数评估的活性。为了解决我们的假设，我们提出了以下目的的研究：1）确定疫苗用TAA表位肽的安全性和耐受性，用于复发性转化膜的儿童； 2）使用IFN-酶 - 连接的免疫点（ELISPOT）和四聚体测定法，定义了疫接种后血液单核细胞对疫苗肽的免疫冲源的速率和大小。还将获得有关对治疗的临床和成像反应，TAA表达与反应之间的关联以及有助于免疫疗法抗性性的机制的初步数据。这项研究的结果是，这将是第一次针对室系膜瘤进行的基于疫苗的试验，它将使我们能够确定这些肿瘤是否有必要进行随后的大型II期试验。