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

基本信息

批准号：
9087366
负责人：
Joseph F Costello
金额：
$ 23.78万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9087366
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 FRAP1 gene Genetic Genetic Markers Germany Glioblastoma Glioma Goals Growth HLA Antigens Health 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 Vaccines World Health Organization actionable mutation antigen binding base chemotherapy exome experience glioma cell line helicase high risk immunogenic improved neoplastic cell novel peptide based vaccine peptide vaccination prevent response temozolomide transcriptome sequencing tumor tumor progression young adult

项目摘要

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（由适用提供）：世界卫生组织（WHO）II级低级神经胶质瘤（LGGS）是生长缓慢的原发性脑肿瘤，这些脑肿瘤往往在年轻人的黄金时段发生在年轻人中。这些患者中的大多数最终都以侵袭性的高级神经胶质瘤（HGG）为肿瘤进展，大多数患者最终屈服于该疾病。免疫治疗方法（例如疫苗）可能特别合适。实际上，我们安全诱导了高危LGG的患者的强大T细胞反应，该患者在靶向与胶质瘤相关抗原（GAAS）的基于肽的疫苗（GAAS）中，HGG在HGG中表达的疫苗（GAAS）高于LGG（NCT00795457和NCT00874861）。这些研究旨在诱导LGG患者的受保护的免疫反应，以防止进展到HGG。但是，进一步的细化将需要更好地表征胶质瘤中可触发疫苗的抗原，这些抗原正在发展为HGG。我们将评估我们的假设，即进展的神经瘤表明在疫苗可靶向GAA的表达曲线中的进化。具体来说，我们将追求以下两个具体目标。 AIM 1：表征具有复发和/或进展的神经胶质瘤中可疫苗靶向GAA的表达。利用来自接受多次复发和/或进展的多项手术的LGG患者的可用成对神经胶质瘤，我们将评估GAAS表达的变化，GAA的表达变化，从中，肿瘤相关的肽（取消）源自复发和进展。我们将同时利用RNA-seq和免疫组织化学。我们的目标是扩展这一特征，以使可用的大约80 GAA失去。这些研究将指导我们为LGG患者选择大多数适当的疫苗接种。 AIM 2：通过分析HLA结合的抗原的分析，确定表达曲线的演变是否与恶性驾驶途径（例如Akt-MTOR）的激活相关。 AIM 1研究将评估存档的组织以表达可用的GAA，而在AIM 2中，我们将通过执行人类白细胞抗原（HLA） - pepitomic-analalyses和T-Cell分析，靶向呈现的分子（预期在循环概述）中，通过进行呈菌丝的分子（预期），该型植物（HLA）抗原（HLA）抗原抗原（HLA）抗原（HLA）抗原（HLA）通过进行循环范围的分子（该分子）进行了调整（该激活），该激活者（即构成）的激活（该激活），该激活者（均预期），该激活者（均预期），该激活者（即在像HGG一样复发的LGG病例中以高水平表示。我们假设致癌途径的激活会导致新型GAA脉冲的HLA呈现，这些新型GAA肿瘤是由于途径激活而在肿瘤细胞中上调的。因此，靶向与LGG向HGG的恶性转化直接相关的抗原可以改善免疫疗法的作用。影响。这项研究将为LGG的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。根据我们的丰富经验和大量LGG案件的可用性，我们有权进行拟议的研究。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma.

DOI：
10.1080/2162402x.2017.1391972
发表时间：
2018
期刊：
Oncoimmunology
影响因子：
7.2
作者：
Dutoit V;Migliorini D;Ranzanici G;Marinari E;Widmer V;Lobrinus JA;Momjian S;Costello J;Walker PR;Okada H;Weinschenk T;Herold-Mende C;Dietrich PY
通讯作者：
Dietrich PY