Peptide vaccine-based immunotherapy for children with recurrent ependymomas.

描述（由申请人提供）：这项新颖的3年R01申请侧重于基于肽的室管膜瘤免疫治疗的试点临床试验，这是最具挑战性的儿童脑肿瘤之一。尽管大约50%的肿瘤可以通过手术和放疗治愈，但仍有相似比例的肿瘤复发并不可避免地进展，尽管随后进行了治疗。受影响的儿童在屈服于难治性肿瘤进展之前，经常经历这些干预措施的累积发病率。因此，需要针对这些肿瘤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，并提出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IL13R¿2，EphA2和survivin，通常远远超过我们在星形细胞瘤中观察到的水平。这表明这些肿瘤可能是免疫疗法非常有希望的候选者。基于这些数据，我们建议对复发性室管膜瘤儿童使用以taa为基础的混合疫苗，联合免疫佐剂（咪喹莫特）。由于肿瘤位置可能对症状性免疫介导的肿瘤肿胀（即假性进展）的潜在影响很大，如果存在强大的瘤内免疫反应，该研究将纳入后窝和非后窝室管膜瘤的单独分层。我们将对两层各12例患者进行每3周皮下TAA表位疫苗接种，共8个疗程，并联合外用咪喹莫特。参与者将通过临床和实验室评估和MR成像评估不良事件、方案限制毒性（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参与者可以接受额外的疫苗接种。这些研究利用了我们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，基于疫苗的免疫疗法不仅可以被证明是安全的儿科室管膜瘤的治疗，而且可以通过免疫和临床参数来评估其活性。为了验证我们的假设，我们提出了以下目的的研究：1)确定复发性室管膜瘤儿童接种TAA表位肽的安全性和耐受性；2)利用IFN-¿-酶联免疫斑点（ELISPOT）和四聚体检测确定疫苗接种后外周血单个核细胞对疫苗肽的免疫应答率和程度。还将获得有关临床和影像学对治疗的反应，TAA表达与反应之间的关联以及促进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首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更大规模的II期试验。

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.