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的一项双机构试点研究，采用疫苗接种方案（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]表位肽，同时肌肉内[i.m.]本发明提供了一种用于在患有世界卫生组织（WHO）II级星形细胞瘤或具有不良预后因素的寡星形细胞瘤的成人中有效诱导抗肿瘤T细胞应答的药物组合物（例如，施用聚ICLC）。这项初步研究的总体目标是收集免疫学和安全性数据，以决定是否需要进行更大规模的临床疗效研究。幕上低级别胶质瘤（LGG）成人患者的不良亚组定义为星形细胞瘤或少星形细胞瘤组织学和以下条件之一：1）年龄40岁，任何程度的切除; 2）年龄18-39岁，不完全切除，或3）年龄18- 39岁，神经外科医生定义的大体全切除，但肿瘤直径4 cm。这些患者在手术后5年内有高达89%的疾病复发风险。然而，LGG的生长速度较慢（与恶性神经胶质瘤相反），应该有足够的时间进行多次免疫接种，这可能导致诱导高水平的GAA特异性免疫。由于LGG患者可能不像高级别胶质瘤患者那样免疫受损，因此他们可能表现出更强的免疫反应。此外，聚ICLC已被证明在临床前脑肿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聚ICLC治疗的组合将安全地诱导有效的抗神经胶质瘤免疫应答。受试者将接受s.c.每3周注射GAA-疫苗8次，并施用聚-ICLC（20 μ g/kg i.m.）在每次疫苗接种当天和接种后第4天。将通过临床访视和MR成像评价受试者的任何可能的不良事件、方案限制性毒性（RLT）和临床应答。表现出任何免疫应答而没有RLT或肿瘤进展的受试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RT将“高风险”LGG患者分为两个队列。我们将用两个特定目的治疗总共18例患者（9例患者/队列），这两个特定目的将确定：1）诱导GAA特异性CD 8 + T细胞应答，2）基于每个队列中RLT频率的提前停止规则的安全性。这项初步研究的数据将使我们能够确定是否有必要进行后续的更大规模的试验。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关于疫苗接种制度的双机构试点研究（皮下注射神经胶质瘤相关抗原衍生的细胞毒性T淋巴细胞表位肽，同时肌肉内施用聚ICLC），其被设计为有效诱导抗肿瘤T淋巴细胞表位。世界卫生组织II级星形细胞瘤或预后不良的寡星形细胞瘤的成人细胞反应。这项初步研究的总体目标是收集免疫学和安全性数据，这些数据将用于决定是否需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.