Antigens for Molecularly Targeted Vaccines for Progressive Glioma

进行性神经胶质瘤分子靶向疫苗的抗原

• 批准号: 8968177
• 负责人: Joseph F Costello
• 金额: $ 19.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968177
• 关键词: Allogenic; Antigen Presentation; Antigen Targeting; Antigens; Archives; Attention; Automobile Driving; Biological Assay; Biotechnology; Characteristics; Data; Development; Diagnosis; Dinucleoside Phosphates; Disease; Epitopes; Evolution; Exhibits; Genetic; Genetic Markers; Germany; Glioblastoma; Glioma; Goals; Growth; HLA Antigens; Immune response; Immunity; Immunization; Immunocompromised Host; Immunohistochemistry; Immunotherapeutic agent; Immunotherapy; Infiltrative Growth; Isocitrate Dehydrogenase; Life; Link; Malignant - descriptor; Malignant Neoplasms; Molecular Profiling; Mutate; Mutation; Oncogenic; Operative Surgical Procedures; Pathway interactions; Patients; Peptides; Primary Brain Neoplasms; Process; Proteins; Proto-Oncogene Proteins c-akt; Qualifying; Radiation therapy; Recurrence; Reporting; Research; Resected; Retinoblastoma; Sampling; Stem cells; T cell response; T-Lymphocyte; TP53 gene; Testing; Time; Tissues; Tumor Antigens; Vaccination; Vaccines; World Health Organization; antigen binding; base; chemotherapy; exome; experience; glioma cell line; helicase; high risk; human FRAP1 protein; immunogenic; improved; mTOR protein; neoplastic cell; novel; peptide based vaccine; prevent; public health relevance; response; temozolomide; transcriptome sequencing; tumor; tumor progression; young adult

 DESCRIPTION (provided by applicant): World Health Organization (WHO) grade II low-grade gliomas (LGGs) are slow-growing primary brain tumors, which tend to occur in young adults at their prime time of life. A majority of these patients eventually have tumor progression as aggressive high-grade glioma (HGG), and most patients eventually succumb to the disease. Immunotherapeutic approaches, such as vaccines, may be particularly appropriate. Indeed, we safely induced a robust T-cell response in patients with high-risk LGG following immunization with peptide-based vaccines targeting glioma-associated antigens (GAAs) expressed at higher levels in HGG than in LGG (NCT00795457 and NCT00874861). These studies are aimed at inducing a protective immune response in LGG patients to prevent progression to HGG. However, further refinement will require better characterization of vaccine-targetable antigens in gliomas that are progressing to HGG. We will evaluate our hypothesis that progressing gliomas demonstrate evolution in the expression profile of vaccine-targetable GAAs. Specifically, we will pursue the following two specific aims. Aim 1: Characterize the expression of vaccine-targetable GAAs in gliomas with recurrence and/or progression. Utilizing available paired gliomas from LGG patients who received multiple surgeries for recurrence and/or progression, we will evaluate changes in the expression of GAAs, from which tumor-associated peptides (TUMAPs) were derived from, in recurrence and progression. We will utilize both RNA-seq and immunohistochemistry. Our goal is to extend this line of characterization for available approximately 80 GAA TUMAPs. These studies will guide us to select most proper TUMAPs for vaccinations in LGG patients. Aim 2: Determine whether the evolution of expression profile is linked with the activation of malignancy-driving pathways (e.g., AKT-mTOR) through analyses of HLA-bound antigens. While Aim 1 studies will evaluate archived tissues for expression of available GAAs, in Aim 2, we will identify novel GAA-epitope peptides (i.e. TUMAPs) by performing human leukocyte antigen (HLA)-peptidomic-analyses and T-cell assays, targeting molecules that are expected to be up-regulated in recurrent cases (due to the activation of oncogenic pathways) and molecules that are expressed at high levels in LGG cases that recur as HGG. We hypothesize that activation of oncogenic pathways leads to HLA-presentation of novel GAA-TUMAPs that are up-regulated in the tumor cell as the result of the pathway-activation. Thus, targeting antigens that are directly relevant to the malignant transformation of LGG to HGG could improve the efficacy of immunotherapy. Impact. This research will inform the development of molecularly defined vaccines for LGG aimed at preventing their progression and malignant transformation to HGG. We are uniquely qualified to pursue the proposed study based on our extensive experience and availability of large numbers of LGG cases.

 描述(申请人提供)：世界卫生组织(WHO)II级低级别胶质瘤(LGG)是一种生长缓慢的原发脑瘤，往往发生在年轻人的黄金时代。这些患者中的大多数最终会出现侵袭性高级别胶质瘤(HGG)的肿瘤进展，大多数患者最终会死于这种疾病。免疫治疗方法，如疫苗，可能特别合适。事实上，我们安全地在高危LGG患者中诱导了强大的T细胞反应，免疫后针对HGG中表达水平高于LGG中的胶质瘤相关抗原(CAS)的多肽疫苗(NCT00795457和NCT00874861)。这些研究旨在诱导LGG患者的保护性免疫反应，以防止进展为HGG。然而，进一步的改进将需要对进展为HGG的胶质瘤的疫苗靶向抗原进行更好的表征。我们将评估我们的假设，即进展性胶质瘤表现出疫苗靶向的GA表达谱的进化。具体地说，我们将追求以下两个具体目标。目的1：研究疫苗靶向的GA基因在复发和/或进展的脑胶质瘤中的表达。利用LGG患者因复发和/或进展而接受多次手术的可用配对胶质瘤，我们将评估肿瘤相关肽(TUMAP)来源的肿瘤相关肽(TUMAP)在复发和进展中的表达变化。我们将同时利用RNA-seq和免疫组织化学。我们的目标是将这一系列表征扩展到现有的大约80个GaA TUMAP。这些研究将指导我们选择最合适的TUMAP用于LGG患者的疫苗接种。目的2：通过分析人类白细胞抗原(HLA)结合抗原，确定基因表达谱的演变是否与肿瘤驱动通路(如AKT-mTOR)的激活有关。虽然目标1的研究将评估存档组织中可用GA的表达，但在目标2中，我们将通过执行人类白细胞抗原(HL A)多肽分析和T细胞分析来识别新的GAA表位多肽(即TUMAP)，目标分子预计在复发病例中上调(由于致癌途径的激活)，以及在LGG病例中高水平表达的分子作为HGG。我们假设致癌通路的激活导致肿瘤细胞中上调的新型GAA-TUMAP的人类白细胞抗原呈递。因此，靶向与LGG向HGG恶变直接相关的抗原可以提高免疫治疗的效果。冲击力。这项研究将为LGG分子定义疫苗的开发提供信息，旨在防止LGG的进展和向HGG的恶变。基于我们丰富的经验和大量LGG病例的可获得性，我们是唯一有资格进行拟议研究的公司。