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（通过应用程序提供）：这种新型R01应用集中于针对低度星形胶质细胞瘤的儿童的基于肽的免疫疗法的创新临床试验，这是最常见的儿童脑肿瘤。尽管手术切除术可治愈良好的表面病变，但浸润或来自深层结构的肿瘤，此类肿瘤 作为视线途径，手术通常无法治愈，并构成了重大管理挑战。进行性肿瘤可能会对常规化学疗法剂和分子靶向剂进行瞬时反应，但是这种病变通常会复发，导致累积发病率，尤其是在多种治疗方案失败的肿瘤中。 According to 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.这些试点研究表明，具有复发性低级星形胶质细胞瘤的儿童，表现出有趣的免疫学和临床反应，其中10名优秀患者中有3名在磁共振成像（MRI）中持续肿瘤退化。在这些数据的基础上，拟议的研究将系统地评估基于肽的疫苗疗法的临床和免疫效率。我们将每3周与肌肉内聚-ICLC一起治疗25例皮下GAA表位疫苗的患者。将评估参与者的限制毒性（RLT）和通过临床，MRI和实验室评估的治疗反应。证明没有RLT的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：肽碱免疫疗法具有足够的临床效率，可以在这些肿瘤中进行更广泛的治疗检查，并且该临床反应将与免疫反应性有关。为了解决这些假设，我们提出了以下目的的研究：1。使用基于MRI的基于MRI的肿瘤反应和无进展生存率的客观测量，确定复发性低级星形胶质细胞瘤儿童的GAA PETITES疫苗的效率。 2。使用IFN-γ-酶联免疫吸附斑点（ELISPOT）和四聚体分析和对相应的免疫学反应，使用IFN-γ-酶联免疫吸收点（ELISPOT）和临床反应，使用IFN-γ-酶联免疫吸收点（ELISPOT）和对疫苗的临床反应相应的免疫反应。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，以及在免疫疗法后进展的肿瘤中免疫镜的机制。这项研究的结果将为确定是否应进一步研究这种方式作为这些挑战肿瘤的潜在疗法。