IMMUNOBIOLOGY OF MALIGNANT GLIOMA

恶性胶质瘤的免疫生物学

• 批准号: 8949252
• 负责人: Gavin Peter Dunn
• 金额: $ 17.17万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8949252
• 关键词: Affinity; Aftercare; Animals; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Binding; Biological; Biology; Brain Neoplasms; CD8B1 gene; CTLA4 gene; Caring; Cell surface; Cells; Central Nervous System Neoplasms; Cervical lymph node group; ChIP-seq; Clinical Trials; DNA Sequence Alteration; Dendritic Cells; Dependency; Development Plans; Disease; Environment; Faculty; Frequencies; Genomic approach; Genomics; Glioblastoma; Glioma; Goals; Haplotypes; Heterogeneity; Human; Immune; Immunobiology; Immunology; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Individual; Investigation; Ligands; Major Histocompatibility Complex; Malignant Glioma; Malignant Neoplasms; Mediating; Mentors; Metastatic Melanoma; Methodology; Modeling; Molecular; Mus; Mutation; Nature; Neuraxis; Neurosurgeon; Neurosurgical Procedures; Newly Diagnosed; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Pre-Clinical Model; Primary Brain Neoplasms; Program Development; Proteins; Publishing; Radiation therapy; Recruitment Activity; Recurrence; Regulation; Research; Research Proposals; Research Training; Role; Signal Transduction; Site; Solid Neoplasm; Staging; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Tumor Antigens; Tumor Immunity; Universities; Washington; Work; base; cancer genomics; cancer immunotherapy; cancer therapy; cancer type; career development; chemoradiation; chemotherapy; exome; functional genomics; immunogenic; inhibitor/antagonist; medical schools; meetings; member; neoplastic cell; neurological pathology; novel; overexpression; programs; public health relevance; receptor; research study; small molecule; structural genomics; success; targeted treatment; temozolomide; therapeutic target; transcription factor; tumor; tumor immunology

 DESCRIPTION (provided by applicant): The candidate is an academic neurosurgeon at Washington University School of Medicine in the Department of Neurological Surgery and Pathology and Immunology and is the first faculty member recruited to the newly- created Center for Human Immunology and Immunotherapy Programs. He has a track record of high-level published research in tumor immunology and cancer genomics. To pursue the goal of successful transition to independent investigation, the candidate has assembled a career development plan with formal coursework, seminars, and meetings focused in genomics and tumor immunity in the central nervous system. The candidate's research training development program will take place at Washington University in St. Louis, which has deep expertise in genomics and immunology. This program will be co-mentored by Drs. Emil Unanue and Andrey Shaw, who together have significant expertise in T cell immunology, antigen presentation, murine immunobiology, and cell signaling that will provide a rich and excellent scientific environment for the proposed work in glioma immunobiology. Additional assistance from Drs. Schreiber, Mardis, Eberlein, and Kim will maximize opportunities to be successful during this transition to independent investigation. The proposed work centers on the immunobiology of malignant glioma. Although glioblastoma, the most aggressive primary brain tumor in patients, has been extensively characterized from a structural genomics standpoint, the "mutation-to-drug" paradigm observed in other cancer types has not been successful in this disease. The inefficacy of targeted therapies in glioblastoma is likely because the tumor cell dependencies are not well understood and because tumors themselves are incredibly heterogeneous. Therefore, alternative approaches to glioblastoma treatment are urgently being tested in clinical trials. Specifically, new "checkpoint blockade" cancer immunotherapy agents that target inhibitory T cell receptors CTLA-4 and PD-1/PD-L1 pathways-which have been successful in other cancers including metastatic melanoma-are entering clinical trials for patients with malignant glioma. The candidate is a site-PI for an anti-PD-L1 trial in human glioblastoma. However, the molecular mechanisms underlying the success of these agents in preclinical models are unclear. Moreover, broader issues in central nervous system immunobiology that has never been well understood-such as antigen presentation-likely will come to bear on the success of checkpoint blockade therapies in brain tumor treatment. Thus, this research proposal focuses on the immunobiology of checkpoint blockade therapy and biology in glioblastoma. Herein, in the first Aim of the research proposal, we will incorporate novel genomics-based approaches to identify tumor-specific antigens expressed by glioma cells and recognized by immune cells following checkpoint therapy. In the second Aim, we will deepen our initial observations that glioma cells express very high levels of the checkpoint therapy target PD-L1 and use a focused functional genomics strategy to dissect the molecular basis of this aberrant overexpression. Finally, in the third Aim we will characterize the role of dendritic cells in the glioma antigen presentation pathway and determine whether they are required in successful checkpoint blockade therapy. Together, these aims will reveal critical mechanistic underpinnings of promising anti-glioma immunotherapeutic approaches and target biological programs that may enhance their efficacy.

 应聘者描述(由申请人提供)：应聘者是华盛顿大学医学院神经外科、病理学和免疫学系的神经外科学者，也是新成立的人类免疫学和免疫疗法中心的第一位教员。他拥有在肿瘤免疫学和癌症基因组学方面发表的高水平研究的跟踪记录。为了追求成功过渡到独立研究的目标，候选人制定了一份职业发展计划，其中包括正式的课程、研讨会和会议，重点是基因组学和中枢神经系统的肿瘤免疫。这位候选人的研究培训开发项目将在圣路易斯的华盛顿大学进行，该大学在基因组学和免疫学方面拥有深厚的专业知识。该项目将由Emil Unanue博士和Andrey Shaw博士共同指导，他们在T细胞免疫学、抗原呈递、小鼠免疫生物学和细胞信号方面拥有丰富的专业知识，这将为拟议中的胶质瘤免疫生物学工作提供丰富和良好的科学环境。Schreiber博士、Mardis博士、Eberlein博士和Kim博士的额外协助将最大限度地增加在向独立调查过渡期间取得成功的机会。拟议的工作重点是恶性胶质瘤的免疫生物学。尽管从结构基因组学的观点来看，胶质母细胞瘤是患者中最具侵袭性的原发脑瘤，但在其他类型的癌症中观察到的“突变到药物”的范例在这种疾病中并不成功。靶向治疗在胶质母细胞瘤中的无效可能是因为肿瘤细胞的依赖性没有被很好地理解，而且肿瘤本身是令人难以置信的异质性。因此，治疗胶质母细胞瘤的替代方法正在紧急进行临床试验。具体地说，以抑制性T细胞受体CTLA-4和PD-1/PD-L1通路为靶点的新型“检查点阻断”癌症免疫治疗剂--已在包括转移性黑色素瘤在内的其他癌症中获得成功--正在进入恶性胶质瘤患者的临床试验。候选药物是针对人脑胶质母细胞瘤的抗PD-L1试验的Site-PI。然而，这些药物在临床前模型中成功的分子机制尚不清楚。此外，中枢神经系统免疫生物学中从未被很好理解的更广泛的问题--如抗原提呈--可能会对检查点阻断疗法在脑肿瘤治疗中的成功产生影响。因此，本研究建议将重点放在检查点阻断治疗的免疫生物学和胶质母细胞瘤的生物学方面。在这里，在研究提案的第一个目标中，我们将结合基于基因组学的新方法来识别由胶质瘤细胞表达并在检查点治疗后被免疫细胞识别的肿瘤特异性抗原。在第二个目标中，我们将深化我们的初步观察，即胶质瘤细胞表达非常高水平的检查点治疗靶标PD-L1，并使用聚焦的功能基因组学策略来剖析这种异常过度表达的分子基础。最后，在第三个目标中，我们将确定树突状细胞在胶质瘤抗原呈递途径中的作用，并确定它们是否是成功的检查点阻断治疗所必需的。总而言之，这些目标将揭示有前景的抗胶质瘤免疫治疗方法的关键机制基础，以及可能增强其疗效的靶向生物学计划。