Peptide vaccine immunotherapy for children with recurrent low-grade astrocytomas

肽疫苗免疫治疗儿童复发性低度星形细胞瘤

• 批准号: 9027315
• 负责人: Ian F. Pollack
• 金额: $ 35.75万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-08 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027315
• 关键词: Address; Antigen Targeting; Antigens; Astrocytoma; Biological Assay; Blindness; Cancer Vaccines; Carboplatin; Cerebrum; Chemotherapy-Oncologic Procedure; Child; Childhood; Childhood Brain Neoplasm; Childhood Glioma; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Disease; Enzymes; Epilepsy; Epitopes; Evaluable Disease; Evaluation; Excision; Foundations; Functional disorder; Glioma; Goals; Image; Immune; Immune response; Immunity; Immunologic Adjuvants; Immunologic Monitoring; Immunosorbents; Immunotherapy; Interferon Type II; Intramuscular; Laboratories; Learning Disabilities; Lesion; Link; Magnetic Resonance Imaging; Measures; Modality; Morbidity - disease rate; Motor; Neoplasm Metastasis; Neurosecretory Systems; Newly Diagnosed; Operative Surgical Procedures; Optics; Participant; Pathway interactions; Patients; Peptide Vaccines; Peptides; Peripheral Blood Mononuclear Cell; Phase II Clinical Trials; Pilot Projects; Poly ICLC; Primary Brain Neoplasms; Primary Neoplasm; Progression-Free Survivals; Proteins; Recurrence; Refractory; Regimen; Resolution; Resources; Safety; Series; Spottings; Structure; Subependymal; Superficial Lesion; T-Lymphocyte Epitopes; Testing; Therapeutic; Toxic effect; Treatment Protocols; Tumor Antigens; Unresectable; Vaccination; Vaccine Therapy; Vaccines; Vinblastine; base; chemotherapy; clinical efficacy; design; diencephalon; disability; innovation; irradiation; novel; overexpression; peptide based vaccine; persistent symptom; public health relevance; response; subcutaneous; survivin; targeted agent; treatment response; tumor; vaccine efficacy; vaccine trial

 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.

 描述（由申请人提供）：这项新颖的 R01 申请重点关注针对患有低度星形细胞瘤（儿童最常见的脑肿瘤）的儿童进行基于肽的免疫疗法的创新 II 期临床试验。虽然手术切除对于界限清楚的浅表病变有疗效，但浸润性或由深层结构产生的肿瘤，例如 作为视神经通路，通常无法通过手术治愈，并且带来了重大的管理挑战。进展性肿瘤可能对常规化疗药物和分子靶向药物有短暂反应，但此类病变经常复发，导致发病率累积，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基于神经胶质瘤相关抗原（GAA）的​​疫苗的安全性和耐受性，该疫苗针对一系列在儿童神经胶质瘤中过度表达的蛋白质，包括新诊断和复发性星形细胞瘤儿童中的 IL13Rα2、EphA2 和 survivin。这些试点研究证明了令人感兴趣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) 中肿瘤持续消退。基于这些数据，拟议的研究将系统评估基于肽的疫苗疗法对患有复发性低级别星形细胞瘤的儿童的临床和免疫学疗效。我们对25名患者进行每3周一次皮下注射GAA表位疫苗接种并联合肌肉注射poly-ICLC治疗8个疗程。将通过临床、MRI 和实验室评估来评估参与者的方案限制毒性 (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患者可以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机构资源，这些资源已整合到临床试验中。拟议的研究将检验以下假设：基于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相关。为了解决这些假设，我们提出以下目标的研究： 1. 使用基于 MRI 的肿瘤反应和无进展生存的客观测量，确定 GAA 肽疫苗接种对复发性低度星形细胞瘤儿童的疗效。 2. 使用 IFN-γ-酶联免疫吸附点 (ELISPOT) 和四聚体测定来表征疫苗后外周血单核细胞针对疫苗靶向抗原的免疫反应的速率和强度，并将免疫反应与疫苗的临床反应相关联。此外，拟议的研究将检查肿瘤中抗原表达与治疗反应之间的关联，以及免疫治疗后进展的肿瘤中的免疫逃逸机制。这项研究的结果将为确定是否应进一步检查这种方式作为这些具有挑战性的肿瘤的潜在疗法提供基础。