Peptide vaccine immunotherapy for children with recurrent low-grade astrocytomas

 描述(由申请人提供)：这一新颖的R01申请专注于基于多肽的免疫治疗儿童低级别星形细胞瘤的创新II期临床试验，低级别星形细胞瘤是儿童最常见的脑瘤。虽然手术切除对于边界清楚的浅表病变是治愈的，但浸润性或起源于深层结构的肿瘤，如 作为视路，往往无法通过手术治愈，并构成重大的管理挑战。进展性肿瘤可能对常规化疗药物和分子靶向药物有短暂的反应，但这种损害经常复发，导致累积发病率，特别是在多种治疗方案失败的肿瘤中。因此，需要新的治疗方法。在这方面，我们的初步研究证明了以胶质瘤相关抗原(GAA)为基础的疫苗的安全性和耐受性，该疫苗针对一系列我们已经证明在儿童胶质瘤中过表达的蛋白，包括IL13Rα2、EphA2和Survivin，用于新诊断和复发的星形细胞瘤儿童。这些初步研究显示了耐人寻味的免疫学和临床反应，特别是在患有复发性低级别星形细胞瘤的儿童中，其中10名可评估患者中有3名在磁共振成像(MRI)上持续肿瘤消退。在这些数据的基础上，这项拟议的研究将系统地评估基于多肽的疫苗治疗复发低级别星形细胞瘤儿童的临床和免疫学疗效。我们将对25例患者进行GAA表位皮下接种，每3周接种一次，共8个疗程，联合肌肉内Poly-ICLC。将通过临床、核磁共振和实验室评估对参与者进行方案限制毒性(RLT)和治疗反应的评估。没有RLT表现出疾病稳定或消退的患者可能会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的机构资源，这些资源被整合到临床试验中。拟议的研究将检验这样一种假设，即基于多肽的免疫疗法具有足够的临床疗效，足以保证对这些肿瘤进行更广泛的治疗检查，并且临床反应将与免疫反应性有关。为了解决这些假设，我们提出了以下目标的研究：1.使用基于MRI的肿瘤反应和无进展生存率的客观指标，确定GAA多肽疫苗对儿童复发性低级别星形细胞瘤的疗效。2.用干扰素-γ-酶联免疫吸附斑点(ELISPOT)法和四聚体试验鉴定疫苗接种后外周血单个核细胞对疫苗靶向抗原的免疫应答的速度和强度，并将免疫学应答与疫苗的临床应答相关联。此外，拟议的研究将检查肿瘤中抗原表达和治疗反应之间的关系，以及免疫治疗后肿瘤进展的免疫逃逸机制。这项研究的结果将为确定是否应该进一步检查这种方式作为这些具有挑战性的肿瘤的潜在治疗方法提供基础。

 DESCRIPTION (provided by applicant): This novel R01 application focuses on an innovative phase II clinical trial of peptide-based immunotherapy for children with low-grade astrocytomas, the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures, such as the optic pathways, are often incurable with surgery and pose a major management challenge. Progressive tumors may respond transiently to conventional chemotherapy agents, and to molecularly targeted agents, but such lesions often recur, leading to cumulative morbidity, particularly in tumors that fail multiple treatment regimens. Accordingly, new treatment approaches are needed. In this regard, our preliminary studies demonstrated the safety and tolerability of glioma-associated antigen (GAA)-based vaccines targeting a series of proteins that we have shown to be overexpressed in pediatric gliomas, including IL13Rα2, EphA2, and survivin, in children with newly diagnosed and recurrent astrocytomas. These pilot studies demonstrated intriguing immunological and clinical responses, particularly in children with recurrent low-grade astrocytomas, in whom 3 of 10 evaluable patients had sustained tumor regression on magnetic resonance imaging (MRI). Building upon these data, the proposed study will systematically evaluate clinical and immunological efficacy of peptide-based vaccine therapy in children with recurrent low-grade astrocytomas. We will treat 25 patients with subcutaneous GAA epitope vaccinations every 3 weeks for 8 courses combined with intramuscular poly-ICLC. Participants will be evaluated for regimen limiting toxicity (RLT) and treatment response by clinical, MRI, and laboratory evaluations. Patients demonstrating 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. The proposed studies will test the hypothesis that peptide-base immunotherapy has sufficient clinical efficacy to warrant broader therapeutic examination in these tumors, and that clinical response will be associated with immunological reactivity. To address these hypotheses, we propose studies with the following aims: 1. Determine the efficacy of vaccination with GAA peptides for children with recurrent low-grade astrocytomas, using objective measures of MRI-based tumor response and progression-free survival. 2. Characterize the rate and magnitude of immune response in post-vaccine peripheral blood mononuclear cells against vaccine-targeted antigens, using IFN-γ-enzyme-linked immunosorbent spot (ELISPOT) and tetramer assays, and correlate immunological response with clinical responses to the vaccine. In addition, the proposed studies will examine associations between antigen expression in the tumor and treatment response, and mechanisms of immune escape in tumors that progress after immunotherapy. The results from this study will provide a basis for determining if this modality should be examined further as a potential therapy for these challenging tumors.