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: 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
• 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

 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级低级别胶质瘤（LGG）是生长缓慢的原发性脑肿瘤，往往发生在年轻人的黄金时期。这些患者中的大多数最终具有作为侵袭性高级别胶质瘤（HGG）的肿瘤进展，并且大多数患者最终死于该疾病。免疫方法，如疫苗，可能特别合适。事实上，我们在用基于肽的疫苗免疫后，安全地诱导了高风险LGG患者的强大T细胞应答，这些疫苗靶向HGG中表达水平高于LGG中表达水平的神经胶质瘤相关抗原（GAA）（NCT 00795457和NCT 00874861）。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，进一步的改进将需要更好地表征进展为HGG的胶质瘤中的疫苗靶向抗原。我们将评估我们的假设，即进展中的胶质瘤表现出疫苗靶向的GAA的表达谱的演变。具体而言，我们将追求以下两个具体目标。目的1：表征复发和/或进展的胶质瘤中疫苗靶向的GAA的表达。利用来自LGG患者的可用配对胶质瘤，这些患者接受了多次手术治疗复发和/或进展，我们将评估GAA表达的变化，肿瘤相关肽（TUMAPs）来自GAA，复发和进展。我们将使用RNA-seq和免疫组织化学。我们的目标是将这条表征线扩展到大约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：确定表达谱的演变是否与恶性驱动途径的激活有关（例如，AKT-mTOR）。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，我们将鉴定新的GAA表位肽（即TUMAP）通过进行人白细胞抗原（HLA）-肽分析和T细胞测定，预期在复发病例中上调的靶向分子（由于致癌途径的激活）和在LGG病例中以高水平表达的分子，其作为HGG复发。我们假设致癌通路的激活导致HLA呈递新型GAA-TUMAPs，其作为通路激活的结果在肿瘤细胞中上调。因此，靶向与LGG向HGG的恶性转化直接相关的抗原可以提高免疫治疗的功效。冲击这项研究将为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病例的可用性，我们有独特的资格进行拟议的研究。

项目成果

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