Duke SPORE in Brain Cancer

描述(申请人提供)：恶性原发脑瘤是导致儿童和年轻人癌症死亡的最常见原因，其死亡人数超过肾癌或黑色素瘤。此外，目前的治疗方法是无能为力的，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，只有少数几种药物被批准在临床上使用。因此，目前对脑瘤的治疗代表了美国目前提供的每一质量调整的生命年所提供的昂贵的医疗治疗。尽管如此，本申请中涉及的肿瘤仍然具有一致的致命性。脑癌中的杜克孢子是一项跨学科的研究提案，它将利用脑瘤生物学的知识，以快速的方式开发各种新的方法来治疗成人原发脑瘤，以便对癌症死亡率和发病率产生立竿见影的影响。反过来，这种孢子将确定在这些患者群体中进行观察的生物学基础，以改进这些治疗方法。这一应用利用了一群有着长期合作和成功转化研究历史的资深科学家和内科科学家，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，这些项目、4个核心和2个项目侧重于吸引新的和有经验的研究人员进入该领域。项目1由John Sampson和Li齐静领导，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EGFRvIII靶向CAR的背景下，是否抑制EGFRvIII转导的T细胞内的miR-23a增强细胞毒性并赋予对宿主免疫抑制的抵抗力。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对II级或III级IDHR132H阳性胶质瘤患者的试点试验中，检查针对肿瘤特异性IDH1R132H突变的多肽疫苗的安全性。由Michael Zalutsky和Darell Bigner领导的项目3将评估211阿特拉标记的抗Tenascin单抗81C6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，并阐明这种疗法产生抗肿瘤免疫反应的机制。每个项目都将经常接受评估，如果达不到其翻译目标，将予以更换。这些项目将得到4个核心的支持，这些核心提供行政支持(核心A)；生物统计学、信息学和数据协调资源(核心B)；临床试验操作基础设施(核心C)；以及生物医学、病理学和免疫监测专门知识(核心D)。将强调杜克大学内部与其他孢子以及政府和非政府组织的合作，以促进孢子研究沿翻译科学连续体的横向和纵向移动。

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.