IMMUNOBIOLOGY OF MALIGNANT GLIOMA

恶性胶质瘤的免疫生物学

• 批准号: 9063099
• 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/9063099
• 关键词: Affinity; Aftercare; Animals; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Binding; Biological; Biology; Brain Neoplasms; CD8B1 gene; CTLA4 gene; Cell surface; Cells; Central Nervous System Neoplasms; Cervical lymph node group; ChIP-seq; Clinical Trials; Cytotoxic T-Lymphocyte-Associated Protein 4; DNA Sequence Alteration; Dendritic Cells; Dependency; Development Plans; Disease; Environment; Faculty; Frequencies; Genomic approach; Genomics; Glioblastoma; Glioma; Goals; Haplotypes; Health; 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; PDCD1LG1 gene; 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; checkpoint therapy; chemoradiation; chemotherapy; exome; functional genomics; immunogenic; medical schools; meetings; member; neoplastic cell; neurological pathology; novel; overexpression; programs; receptor; research study; small molecule inhibitor; standard of care; structural genomics; success; targeted agent; targeted treatment; temozolomide; therapeutic target; transcription factor; tumor; tumor heterogeneity; 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.

 描述（由申请人提供）：该候选人是华盛顿大学医学院神经外科和病理学与免疫学系的学术神经外科医生，是新成立的人类免疫学和免疫治疗项目中心招募的第一位教员。他在肿瘤免疫学和癌症基因组学方面发表了高水平的研究成果。为了追求成功过渡到独立调查的目标，候选人已经制定了职业发展计划，包括正式的课程，研讨会和会议，重点是中枢神经系统的基因组学和肿瘤免疫。候选人的研究培训发展计划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具有深厚的专业知识。该计划将由Emil Unanue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传导方面具有重要的专业知识，这将为胶质瘤免疫生物学的拟议工作提供丰富而优秀的科学环境。Schreiber，Mardis，Eberlein和Kim博士的额外协助将最大限度地提高在向独立调查过渡期间取得成功的机会。建议的工作中心恶性胶质瘤的免疫生物学。虽然胶质母细胞瘤是患者中最具侵袭性的原发性脑肿瘤，但从结构基因组学的角度来看，已经对其进行了广泛的表征，但在其他癌症类型中观察到的“突变-药物”范式在这种疾病中并不成功。胶质母细胞瘤靶向治疗的无效可能是因为对肿瘤细胞的依赖性还没有很好的了解，而且肿瘤本身具有令人难以置信的异质性。因此，胶质母细胞瘤治疗的替代方法迫切需要在临床试验中进行测试。具体来说，靶向抑制性T细胞受体CTLA-4和PD-1/PD-L1通路的新型“检查点阻断”癌症免疫治疗药物--在包括转移性黑色素瘤在内的其他癌症中已经取得成功--正在进入恶性胶质瘤患者的临床试验。该候选人是一项在人胶质母细胞瘤中进行的抗PD-L1试验的研究中心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，如抗原呈递，可能会影响检查点阻断疗法在脑肿瘤治疗中的成功。因此，这项研究计划的重点是检查点阻断治疗的免疫生物学和胶质母细胞瘤的生物学。在本文中，在研究提案的第一个目标中，我们将采用新的基于基因组学的方法来鉴定胶质瘤细胞表达的肿瘤特异性抗原，并在检查点治疗后被免疫细胞识别。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点PD-L1，并使用集中的功能基因组学策略来剖析这种异常过表达的分子基础。最后，在第三个目标中，我们将描述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。总之，这些目标将揭示有希望的抗胶质瘤免疫方法和靶向生物学程序的关键机制基础，可能会提高其疗效。