TRANSLATIONAL CLINICAL TRIALS FOR PRIMARY CNS TUMORS

项目3。原发性CMST肿瘤的转化临床试验。大卫A.里尔登，医学博士，项目负责人 尽管有标准的术后细胞毒性放疗和化疗， 原发性脑肿瘤仍然令人沮丧。为了克服传统方法的局限性，我们 开发了包括针对肿瘤特异性EGFRvIII突变体的肽疫苗的创新疗法 受体和区域施用的放射性标记的抗腱生蛋白单克隆抗体，其各自具有 基于高度令人鼓舞的生存率改善，进入多中心、随机III期研究， 在我们中心进行的临床试验中观察到的毒性极小。在本申请中，我们将进一步 通过扩大我们的免疫治疗计划来推进这些方法：评估剂量密集型 替莫唑胺或贝伐单抗增强EGFRvIII疫苗免疫原性;评估我们的EGFRvIII 在不可切除的肿瘤患者中使用疫苗;并评估一种新的脑肿瘤干细胞RNA脉冲 树突状细胞疫苗接种策略。我们还将评估几种肿瘤特异性单克隆抗体免疫毒素构建体 开发并在我们的中心进行了临床前广泛评价的靶向EGFRvIII的药物（MR 1 -1; BB-IND# 12589）、野生型EGFR和EGFRvIII（D2 C7）、糖蛋白非转移性B（F6 V）、神经节苷脂3 '-isoLM 1 和3 '6'-isoLD 1，以及软骨素蛋白聚糖硫酸盐（Me 1 -14，Me 1 -5，和9.2.27）。我们将 我还评估了三种新的，区域管理的治疗策略，包括俄歇电子标记 针对EGFR的模块化重组转运蛋白（MRT）（项目1），一种重组脊髓灰质炎病毒/鼻病毒 通过NCI RAID计划生产的结构，以及用于对流的新型球囊导管装置 增强递送（CED）。最后，我们还将研究CED的潜在局限性， 放射性标记的高分子量标记物，例如通过正电子发射断层摄影术成像的124 L-白蛋白。 我们假设，创新的治疗方法，适当的临床试验资格，严格的目标验证， 增强的给药策略将改善恶性肿瘤患者的总体生存率和生活质量， 胶质瘤 我们的具体目标是： 1.进行I期和II期临床试验，以评估创新疗法，包括 疫苗免疫治疗策略，新型免疫毒素，模块化重组转运蛋白， 转基因脊髓灰质炎病毒，可以提高恶性胶质瘤的总体生存率和生活质量 病人; 2.进行I期和II期临床试验，以确定增强局部给药 可以获得新的治疗方法，以提高总生存率和生活质量， 恶性胶质瘤患者。 相关性（参见说明）： 项目3中的临床调查研究均旨在开发更有效、毒性更低的药物 恶性脑肿瘤的治疗方法

Project 3. Translational Clinical Trials for Primary CMSTumors. David A. Reardon, M.D., Project Leader Despite standard post-surgical cytotoxic radiotherapy and chemotherapy, the outcome for patients with primary brain tumors remains dismal. To overcome the limitations of conventional approaches, we have developed innovative therapeutics including a peptide vaccine against the tumor-specific EGFRvlll mutant receptor and a regionally administered, radiolabeled anti-tenascin monoclonal antibody, that have each advanced to multi-center, randomized phase III studies based on highly encouraging improved survival and minimal toxicity observed in clinical trials conducted at our center. In this application, we will further advance these approaches by expanding our immunotherapy program to: evaluate dose intensive temozolomide or bevacizumab to enhance EGFRvlll vaccine immunogenicity; evaluate our EGFRvlll vaccine among patients with non-resectable tumors; and evaluate a novel brain tumor stem cell RNA-pulsed dendritic cell vaccination strategy. We will also evaluate several tumor-specific MAb immunotoxin constructs developed and extensively evaluated preclinically at our center that target EGFRvlll (MR1-1; BB-IND# 12589), wild-type EGFR and EGFRvlll (D2C7), glycoprotein non-metastatic B (F6V), gangliosides 3'-isoLM1 and 3'6'-isoLD1, and chondroitin proteoglycan sulfate (Me1-14, Me1-5, and 9.2.27), respectively. We will also evaluate three novel, regionally administered therapeutic strategies including Auger electron-labeled modular recombinant transporters (MRT) against EGFR (Project 1), a recombinant poliovirus/rhinovirus construct produced through the NCI RAID program, and a novel balloon catheter device for convection enhanced delivery (CED). Finally, we will also investigate potential limitations of CED by co-infusing a radiolabeled high molecular weight marker such as 124l-albumin imaged by positron emission tomography. We hypothesize that innovative therapeutics, appropriate clinical trial eligibility, rigorous target validation, and enhanced delivery strategies will improve overall survival and quality of life for patients with malignant glioma. Our Specific Aims are: 1. To conduct Phase I and II clinical trials to assess whether innovative therapeutics including vaccine immunotherapy strategies, novel immunotoxins, modular recombinant transporters and genetically modified poliovirus, can improve overall survival and quality of life for malignant glioma patients; 2. To conduct Phase I and II clinical trials designed to determine whether enhanced local delivery of novel therapeutics can be achieved in order to improve overall survival and quality of life for malignant glioma patients. RELEVANCE (See instructions): The clinical investigation studies in Project 3 are all designed to develop more effective and less toxic treatments for malignant brain tumors.