Duke SPORE in Brain Cancer

杜克孢子在脑癌中的应用

• 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
• 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

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，死亡人数超过肾癌或黑色素瘤。此外，目前的治疗是失能的，并受到非特异性毒性的限制。尽管进行了数百次临床试验，但在上个世纪，只有少数药物被批准用于临床。因此，目前的脑肿瘤治疗代表了美国目前提供的每质量调整生命年节省的最昂贵的医学治疗。尽管如此，本申请中所述的肿瘤仍然是一致致命的。脑癌的杜克孢子是一个跨学科的研究提案，将利用脑肿瘤生物学的知识，以迅速的方式开发多种新方法来治疗成人原发性脑肿瘤，以便对癌症死亡率和发病率产生直接影响。反过来，该SPORE将确定在这些患者人群中进行观察的生物学基础，以改善这些治疗。该应用程序利用了一组具有长期合作历史和成功转化研究的资深科学家和医生-科学家，通过整合新的杜克癌症研究所并仔细评估和监测4个项目，4个核心和2个项目来实现这些目标，重点是吸引新的和有经验的研究人员进入该领域。由John Sampson和Qi-Jing Li领导的项目1将研究EGFRvIII嵌合抗原T细胞受体（CAR）治疗对肿瘤异质性的影响，以及在IC递送的EGFRvIII靶向CAR的背景下，EGFRvIII-CAR转导的T细胞内的miR-23 a抑制是否增强细胞毒性并赋予对宿主免疫抑制的抗性。由Hai Yan和John Sampson领导的项目2将在正式的临床前毒性研究和II级或III级IDHR 132 H阳性胶质瘤患者的试点试验中检查针对肿瘤特异性IDH 1 R132 H突变的肽疫苗的安全性。由Michael Zalutsky和Darell Bigner领导的项目3将评估211 At标记的抗腱生蛋白MAb 81 C6在新诊断的GBM患者中的治疗潜力。由Matthias Gromeier和Allan Friedman领导的项目4将使用一种有前途的溶瘤脊髓灰质炎病毒进行临床试验，并阐明这种疗法产生抗肿瘤免疫反应的机制。每个项目将经常进行评估，如果不符合其翻译目标，将被替换。这些项目将得到4个核心的支持，即提供行政支持（核心A）;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）以及生物标本、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、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的横向和纵向移动。