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（由申请人提供）：世界卫生组织（WHO）II级低级别神经胶质瘤（LGG）是生长缓慢的原发性脑肿瘤，往往发生在生命黄金时期的年轻人中。这些患者中的大多数最终肿瘤进展为侵袭性高级别神经胶质瘤（HGG），并且大多数患者最终死于该疾病。免疫治疗方法，例如疫苗，可能特别合适。事实上，在使用针对神经胶质瘤相关抗原（GAA）的​​肽疫苗进行免疫接种后，我们安全地诱导了高危 LGG 患者强烈的 T 细胞反应，该疫苗在 HGG 中的表达水平高于 LGG（NCT00795457 和 NCT00874861）。这些研究旨在诱导 LGG 患者产生保护性免疫反应，以防止进展为 HGG。然而，进一步细化需要更好地表征正在进展为 HGG 的神经胶质瘤中的疫苗靶向抗原。我们将评估我们的假设，即进展性神经胶质瘤证明了疫苗可靶向的 GAA 表达谱的进化。具体来说，我们将追求以下两个具体目标。目标 1：表征具有复发和/或进展的神经胶质瘤中疫苗可靶向的 GAA 的表达。利用来自因复发和/或进展而接受多次手术的 LGG 患者的可用配对神经胶质瘤，我们将评估复发和进展中 GAA 表达的变化，肿瘤相关肽 (TUMAP) 来源于 GAA。我们将利用 RNA-seq 和免疫组织化学。我们的目标是将这一特征系列扩展到可用的大约 80 个 GAA TUMAP。这些研究将指导我们选择最合适的 TUMAP 来为 LGG 患者接种疫苗。目标 2：通过分析 HLA 结合抗原，确定表达谱的演变是否与恶性肿瘤驱动途径（例如 AKT-mTOR）的激活有关。虽然目标 1 研究将评估存档组织中可用 GAA 的表达，但在目标 2 中，我们将通过进行人类白细胞抗原 (HLA) 肽组学分析和 T 细胞分析来鉴定新型 GAA 表位肽（即 TUMAP），靶向预期在复发病例中上调的分子（由于致癌途径的激活）和 在复发为 HGG 的 LGG 病例中表达水平较高。我们假设致癌途径的激活导致新型 GAA-TUMAP 的 HLA 呈递，由于途径激活，这些 GAA-TUMAP 在肿瘤细胞中上调。因此，针对与 LGG 向 HGG 恶性转化直接相关的抗原可以提高免疫治疗的功效。影响。这项研究将为 LGG 分子定义疫苗的开发提供信息，旨在防止其进展和恶性转化为 HGG。基于我们丰富的经验和大量 LGG 案例的可用性，我们具有独特的资格来开展拟议的研究。