TRANSLATIONAL CLINICAL TRIALS FOR PRIMARY CNS TUMORS

项目3：原发肿瘤的转化性临床试验。David A.Reardon，医学博士，项目负责人 尽管手术后进行了标准的细胞毒性放射治疗和化疗，但对 原发脑瘤仍然令人沮丧。为了克服传统方法的局限性，我们有 开发了创新的治疗方法，包括针对肿瘤特异性EGFRv11突变体的多肽疫苗 受体和区域注射的放射性标记的抗Tenascin单抗，它们各自具有 基于高度鼓舞人心的改善存活率的多中心随机第三阶段研究 在我们中心进行的临床试验中观察到的毒性最小。在本应用程序中，我们将进一步 通过扩大我们的免疫治疗计划来促进这些方法：评估剂量密集型 替莫唑胺或贝伐单抗可增强EGFRv11疫苗的免疫原性；评估我们的EGFRv11 不可切除肿瘤患者的疫苗；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抗免疫毒素的构建。 在我们的中心开发和广泛的临床前评估，目标是EGFRv11(MR1-1；BB-Ind# 12589)、野生型EGFR和EGFR v11(D2C7)、非转移性糖蛋白B(F6V)、神经节苷脂3‘-isLM1 和3‘6’-isLD1和硫酸软骨素蛋白多糖(ME1-14、ME1-5和9.2.27)。我们会 我还评估了三种新的区域给药治疗策略，包括Auger电子标记 针对重组脊髓灰质炎病毒/鼻病毒EGFR的模块化重组转运体(MRT)(项目1) 通过NCI RAID计划生产的结构和一种用于对流的新型球囊导管装置 增强交付(CED)。最后，我们还将研究CED的潜在局限性，方法是将 放射性标记的高分子量标记物，如124l-白蛋白，经正电子发射断层扫描成像。 我们假设创新疗法，适当的临床试验资格，严格的靶点验证， 改进的交付策略将改善恶性肿瘤患者的总体生存和生活质量 神经胶质瘤。 我们的具体目标是： 1.进行第一期和第二期临床试验，以评估创新疗法是否包括 疫苗免疫治疗策略，新型免疫毒素，模块化重组转运体和 转基因脊髓灰质炎病毒可以提高恶性胶质瘤的总体存活率和生活质量 患者； 2.进行第一阶段和第二阶段临床试验，以确定加强当地给药是否 可以实现新的治疗方法，以提高患者的总体存活率和生活质量 恶性胶质瘤患者。 相关性(请参阅说明)： 项目3中的临床调查研究都是为了开发更有效和毒性更低的 恶性脑瘤的治疗。

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.