A Bi-Institutional Pilot Study of Vaccinations for Patients with Low Grade Glioma

描述(由申请人提供)：这是匹兹堡大学癌症研究所和维克森林大学综合癌症中心之间关于疫苗接种制度的双机构试点研究(皮下注射胶质瘤相关抗原[GAA]衍生的细胞毒性T淋巴细胞[CTL]表位多肽，同时肌肉注射[I.M.]多聚ICLC)，旨在有效地在患有世界卫生组织(WHO)II级星形细胞瘤或预后因素较差的寡星形细胞瘤的成年人中诱导抗肿瘤T细胞反应。这项初步研究的总体目标是收集免疫学和安全性数据，以决定是否有必要进行更大规模的临床疗效研究。幕上低级别胶质瘤(LGG)的不良亚型是指具有星形细胞瘤或少发星形细胞瘤组织学特征，且有下列条件之一的患者：1)年龄40岁，行任何范围的切除；2)年龄18-39岁，行不完全切除；或3)年龄18-39岁，行神经外科医生定义的大体全切除，但肿瘤直径为4 cm。这些患者在手术后5年内疾病复发的风险高达89%。然而，与恶性胶质瘤相比，LGG的生长速度较慢，应该有足够的时间进行多次免疫，这可能会导致高水平的GAA特异性免疫诱导。由于LGG患者可能不像高级别胶质瘤患者那样免疫受损，他们可能会表现出更大的免疫反应。此外，Poly-ICLC已被证明在临床前脑瘤模型中增强疫苗效果，并且在恶性胶质瘤患者中是安全的。因此，我们假设这种形式的疫苗与Poly-ICLC治疗相结合将安全地诱导出强大的抗胶质瘤免疫反应。参与者将接受S.C.的治疗。每3周注射一次GAA疫苗，共8次，并将给予Poly-ICLC(20&lt；g/kg肌肉注射)。在每种疫苗接种后的当天和第4天。参与者将通过临床访问和磁共振成像来评估任何可能的不良事件、方案限制毒性(RLT)和临床反应。没有RLT或肿瘤进展的任何免疫反应的参与者可以接受额外的疫苗接种。我们还将敏锐地辨别患者先前(术后)的放射治疗(RT)是否会影响拟议疫苗的安全性和免疫反应。为此，我们将根据患者是否接受术后放疗将患有“高危”LGG的患者分成两组。我们将针对总共18名患者(9名患者/队列)进行两个特定目标的治疗，以确定：1)诱导GAA特异性CD8+T细胞反应；2)基于每个队列中RLT频率的早期停药规则的安全性。这项先导性研究的数据将使我们能够确定是否有必要进行更大规模的试验。公共卫生相关性：这是匹兹堡大学癌症研究所和维克森林大学综合癌症中心之间的一项双机构试点研究，该研究采用了一种疫苗接种方案(皮下注射胶质瘤相关抗原衍生的细胞毒性T淋巴细胞表位多肽，同时肌肉注射Poly-ICLC)，旨在有效地诱导预后因素较差的成年世界卫生组织II级星形细胞瘤或寡星形细胞瘤患者的抗肿瘤T细胞反应。这项初步研究的总体目标是收集免疫学和安全性数据，这些数据将被用来决定是否有必要进行更大规模的临床疗效研究。

DESCRIPTION (provided by applicant): This is a bi-institutional pilot study between the University of Pittsburgh Cancer Institute and the Comprehensive Cancer Center of Wake Forest University of a vaccination regime (subcutaneous injections of glioma-associated antigen [GAA]-derived cytotoxic T-lymphocyte [CTL] epitope-peptides with simultaneous intramuscular [i.m.] administration of poly-ICLC) that is designed to efficiently induce anti-tumor T-cell responses in adults with either World Health Organization (WHO) grade II astrocytoma or oligoastrocytoma with poor prognostic factors. The overall objective of this pilot study is to collect immunological and safety data to decide whether a larger study of clinical efficacy is warranted. Unfavorable subsets of adult patients with supratentorial low grade glioma (LGG) are defined as ones with astrocytoma or oligoastrocytoma histology and either one of the following conditions: 1) age e 40 with any extent resection; 2) age 18-39 with incomplete resection, or 3) age 18-39 with neurosurgeon- defined gross total resection but the tumor size is e 4 cm in diameter. These patients have as high as an 89% risk of suffering disease recurrence at 5 years following surgery. However, the slower growth rate of LGG (in contrast to malignant gliomas) should allow sufficient time to administer multiple immunizations, which may lead to the induction of high levels of GAA-specific immunity. Because patients with LGG are likely not to be as immune-compromised as patients with higher-grade gliomas, they may exhibit greater immunological responses. In addition, poly-ICLC has been demonstrated to enhance the vaccine effects in preclinical brain tumor models, and to be safe in malignant glioma patients. Therefore, we hypothesize that this form of vaccine in combination with poly-ICLC treatment will safely induce potent anti-glioma immune response. Participants will be treated with s.c. injections of GAA-vaccines every 3 weeks for 8 times and poly-ICLC will be administered (20 <g/kg i.m.) on the day of and on day 4 after each vaccine. Participants will be evaluated for any possible adverse event, regimen limiting toxicity (RLT), and clinical response by clinic visits and MR imaging. Participants who demonstrate any immunological response without RLT or tumor progression may undergo additional vaccinations. We will also be keen discerning whether the patient's prior (postoperative) radiation therapy (RT) can influence the safety of, and immune responses against the proposed vaccines. To this end, we will stratify patients with "high risk" LGG into two cohorts based on whether patients received postoperative RT. We will treat a total of 18 patients (9 patients/cohort) with two Specific Aims that will determine: 1) induction of GAA-specific CD8+ T cell responses, and 2) safety with an early stopping rule based on the frequency of RLT in each cohort. Data from this pilot study will allow us to determine whether a subsequent lager trial is warranted. PUBLIC HEALTH RELEVANCE: This is a bi-institutional pilot study between the University of Pittsburgh Cancer Institute and the Comprehensive Cancer Center of Wake Forest University of a vaccination regime (subcutaneous injections of glioma-associated antigen-derived cytotoxic T-lymphocyte epitope-peptides with simultaneous intramuscular administration of poly-ICLC) that is designed to efficiently induce anti-tumor T-cell responses in adults with World Health Organization grade II astrocytoma or oligoastrocytoma with poor prognostic factors. The overall objective of this pilot study is to collect immunological and safety data that will be used to decide whether a larger study of clinical efficacy is warranted.