Duke SPORE in Brain Cancer

杜克孢子在脑癌中的应用

基本信息

批准号：
9333295
负责人：
FRANCIS ALI-OSMAN
金额：
$ 229.8万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333295
关键词：
Address Adult Alpha Particle Emitter Alpha Particles Antibodies Antigens Astatine Autoimmunity Basic Science Beta Particle Biological Biometry Brain Brain Neoplasms Cancer Etiology Cessation of life Clinic Clinical Clinical Data Clinical Research Clinical Trials Collaborations Communication Data Databases Development Dose Dose-Limiting Ensure Evaluation Faculty Fostering Glioblastoma Glioma Goals Government Histologic Human Human poliovirus I131 isotope Immune Immune response Immunologic Monitoring Immunosuppression Immunotherapy Inflammatory Informatics Infusion procedures Injectable Institutes Interdisciplinary Study Investigational New Drug Application Isocitrate Dehydrogenase Knowledge Label Leadership Link Longevity Lutetium Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Mediating Medical MicroRNAs Modeling Monitor Monoclonal Antibody 81C6 Morbidity - disease rate Movement Mus Mutation Newly Diagnosed Normal tissue morphology Office of Administrative Management Oncolytic Outcome Pathology Patients Peptide Vaccines Peptides Phase Physicians Pilot Projects Population Primary Brain Neoplasms Qi Quality-Adjusted Life Years Radiation Radiation therapy Receptor Cell Recombinants Recording of previous events Recruitment Activity Recurrence Renal carcinoma Reporting Reproduction spores Research Research Infrastructure Research Personnel Research Proposals Resectable Resistance Resources Safety Sampling Scientist Senior Scientist Series Specificity Surgically-Created Resection Cavity T-Lymphocyte Tenascin Therapeutic Therapeutic Agents Tissues Toxic effect Transforming Growth Factors Transgenic Organisms Translating Translational Research Tumor Biology United States Food and Drug Administration Vaccination Vaccines Wit cancer cell career development cellular transduction childhood cancer mortality chimeric antigen receptor clinical infrastructure clinical investigation combat combinatorial cytotoxic cytotoxic radiation cytotoxicity design epidermal growth factor receptor VIII experience immunogenicity improved innovation melanoma mortality novel strategies novel therapeutics oncolytic virotherapy operation patient population peptide vaccination phase 1 study pilot trial preclinical study preclinical toxicity programs public health relevance response tumor tumor growth tumor heterogeneity young adult

项目摘要

DESCRIPTION (provided by applicant): Malignant primary brain tumors are the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Moreover, current therapy is incapacitating and limited by non-specific toxicity. Despite hundreds of clinical trials, only a handful of agents have been approved for use in the clinic in the last century. As a result, current therapy for brain tumors represents the mos expensive medical therapy per quality-adjusted life-year saved currently provided in the US. Despite all of this, the tumors addressed in this application remain uniformly lethal. The Duke SPORE in Brain Cancer is an interdisciplinary research proposal that will use knowledge of brain tumor biology to develop diverse new approaches to the treatment of adult primary brain tumors in an expeditious fashion in order to have an immediate impact on cancer mortality and morbidity. In turn, this SPORE will determine the biological basis for observations made in these patient populations in order to improve these treatments. This application leverages a group of senior scientists and physician-scientists with a long history of collaboration and successful translational research to accomplish these goals through integration within the new Duke Cancer Institute and careful evaluation and monitoring of 4 Projects, 4 Cores and 2 Programs focused on attracting new and experienced investigators to this field. Project 1, led by John Sampson and Qi-Jing Li, will examine the impact of EGFRvIII-chimeric antigen T-cell receptor (CAR) therapy on tumor heterogeneity and whether miR-23a inhibition within EGFRvIII-CAR transduced T cells enhances cytotoxicity and confers resistance to host immunosuppression in the context of an IC delivered EGFRvIII- targeted CAR. Project 2, led by Hai Yan and John Sampson, will examine the safety of a peptide vaccine targeting the tumor-specific IDH1R132H mutation in formal preclinical toxicity studies and a pilot trial in patients with grade II or III IDHR132H positive glioma. Project 3, led by Michael Zalutsky and Darell Bigner, will evaluate the therapeutic potential of 211Atlabeled anti-tenascin MAb 81C6 in newly diagnosed GBM patients. Project 4, led by Matthias Gromeier and Allan Friedman, will conduct a clinical trial wit a promising oncolytic poliovirus and elucidate mechanisms by which this therapy generates an anti-tumor immune response. Each project will be evaluated frequently and replaced if not meeting its translational goals. The projects will be supported by 4 Cores that provide Administrative support (Core A); Biostatistics, Informatics, and Data Coordination resources (Core B); Clinical Trial Operations infrastructure (Core C), and Biospecimen, Pathology, and Immune Monitoring expertise (Core D). Collaborations within Duke, with other SPOREs, and government and non-government organizations will be emphasized to facilitate movement of SPORE research horizontally and vertically along the translational science continuum.

描述（由申请人提供）：恶性原发性脑肿瘤是儿童和年轻人癌症死亡的最常见原因，比肾癌或黑色素瘤造成的死亡人数更多。此外，目前的治疗是无能力的并且受到非特异性毒性的限制。尽管进行了数百项临床试验，但上个世纪只有少数药物被批准用于临床。因此，目前的脑肿瘤治疗是美国目前提供的每挽救质量调整生命年最昂贵的药物治疗。尽管如此，本申请中涉及的肿瘤仍然是一致致命的。杜克脑癌 SPORE 是一项跨学科研究计划，将利用脑肿瘤生物学知识，快速开发多种治疗成人原发性脑肿瘤的新方法，以便对癌症死亡率和发病率产生立竿见影的影响。反过来，该孢子将确定在这些患者群体中进行观察的生物学基础，以改进这些治疗。该应用程序利用了一群具有悠久合作历史和成功转化研究的资深科学家和医师科学家，通过与新杜克癌症研究所的整合以及对 4 个项目、4 个核心和 2 个项目的仔细评估和监控来实现这些目标。吸引新的和经验丰富的研究人员进入该领域。项目 1 由 John Sampson 和 Qi-Jing Li 领导，将研究 EGFRvIII 嵌合抗原 T 细胞受体 (CAR) 疗法对肿瘤异质性的影响，以及 EGFRvIII-CAR 转导的 T 细胞内的 miR-23a 抑制是否会增强细胞毒性并赋予细胞毒性。在 IC 递送 EGFRvIII 靶向 CAR 的情况下对宿主免疫抑制产生耐药性。项目 2 由 Hai Yan 和 John Sampson 领导，将在正式的临床前毒性研究和针对 II 级或 III 级 IDHR132H 阳性神经胶质瘤患者的试点试验中检查针对肿瘤特异性 IDH1R132H 突变的肽疫苗的安全性。项目 3 由 Michael Zalutsky 和 Darell Bigner 领导，将评估 211At 标记的抗生腱蛋白 MAb 81C6 对新诊断 GBM 患者的治疗潜力。由 Matthias Gromeier 和 Allan Friedman 领导的项目 4 将针对一种有前景的溶瘤脊髓灰质炎病毒进行临床试验，并阐明该疗法产生抗肿瘤免疫反应的机制。每个项目都会经常被评估，如果没有达到其转化目标，就会被替换。这些项目将得到 4 个提供行政支持的核心（核心 A）的支持；生物统计学、信息学和数据协调资源（核心 B）；临床试验运营基础设施（核心 C）以及生物样本、病理学和免疫监测专业知识（核心 D）。将强调杜克大学内部与其他 SPORE 以及政府和非政府组织的合作，以促进 SPORE 研究沿着转化科学连续体水平和垂直发展。