Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors

原发性和转移性中枢神经系统肿瘤的疫苗免疫毒素和放射免疫治疗

• 批准号: 8508884
• 负责人: DARELL D BIGNER
• 金额: $ 305.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-11 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508884
• 关键词: Aftercare; Albumins; Alpha Particles; Animal Model; Antigens; Astatine; Astrocytoma; Autoimmunity; Biostatistics Core; Brain; Brain Neoplasms; Breast; Breast Carcinoma; Catheters; Central Nervous System Neoplasms; Cerebrospinal Fluid; Clinical; Clinical Trials; Collaborations; Computational algorithm; Conduct Clinical Trials; Control Groups; Convection; Cytomegalovirus; Discipline of Nuclear Medicine; Dose; Eligibility Determination; Epidermal Growth Factor Receptor; Exotoxins; External Beam Radiation Therapy; Gadolinium DTPA; Glioblastoma; Hematopoietic; Image; Immune response; Immunologic Monitoring; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Immunotoxins; Informatics; Intrathecal Chemotherapy; Label; Long-Term Survivors; Lung; Lymphopenia; Malignant - descriptor; Malignant Neoplasms; Metastatic Neoplasm to the Leptomeninges; Methodology; Methods; Modeling; Monitor; Monoclonal Antibodies; Mus; Newly Diagnosed; Pathway interactions; Patients; Performance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physicians; Positron-Emission Tomography; Primary Brain Neoplasms; Pseudomonas; Radiation; Radiation therapy; Radioactivity; Radioimmunotherapy; Radioisotopes; Radiometry; Randomized; Recording of previous events; Recovery; Recurrence; Refractory; Regulatory T-Lymphocyte; Safety; Scientist; Senior Scientist; T-Lymphocyte; Targeted Radiotherapy; Tissue Banking; Tissue Banks; Toxic effect; Trastuzumab; Tumor Immunity; Tumor Tissue; Vaccinated; Vaccination; Vaccines; Vertebral column; arm; bevacizumab; biobank; clinical trials in animals; cytotoxic; dehalogenation; design; effective therapy; improved; lung Carcinoma; meetings; neoplastic cell; neuro-oncology; novel; novel strategies; outcome forecast; overexpression; panitumumab; receptor; standard of care; statistics; temozolomide; tumor

DESCRIPTION (provided by applicant): This is an application to the NCI from a group of senior scientists and physician/scientists with a long history of collaboration who proposes novel approaches for treatment of two of the conditions in neuro-oncology which are most refractory to treatment, neoplastic meningitis (NM) and glioblastoma multiforme (GBM). NM is characterized by the dissemination of malignant tumor cells within the leptomeningeal space and metastatic spread through the cerebrospinal fluid along the brain and spine. NM from carcinoma of the breast and lung are the most common subtypes. Prognosis of NM is grim with median survival of 2 to 6 months. Current therapy is ineffective and limited by toxicity to the CNS. GBM is the most common and most malignant primary brain tumor. Despite hundreds of clinical trials, only two agents, temozolomide and bevacizumab, have been approved for treatment by the FDA in the last decade. Less than half of patients treated with these two agents respond. Recurrence after treatment is almost universal and median survival is 15 to 18 months with few long-term survivors. Targeted immunotherapy with monoclonal antibodies (MAbs) or their fragments armed with Astatine 211 or Pseudomonas exotoxin for the treatment of NM or GBM is proposed in Projects 1 and 3. In Project 2 vaccine approaches against the ubiquitous antigens from CMV in GBM are proposed to be improved by decreasing immunosuppressive regulatory T-cells or TReg in the setting of temozolomide-induced lymphopenia by administering a specific humanized MAb reactive with the IL-2Ra receptor. Project 1, led by Michael Zaiutsky, is entitled "Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Labeled with Alpha Particle Emitting At." Project 2, led by John Sampson, and is entitled, "Targeting Immunosuppression Pathways to Enhance Brain Tumor Immunotherapy." Project 3, led by Darell Bigner, and is entitled, "EGFRwt and EGFRvlll Dual-Specific Immunotoxin for Glioblastoma Multiforme." These three projects will be supported by an Imaging Core, Daniel Barboriak, Core Director; a Clinical Support Core for biostatistics, informatics, immune monitoring, and a brain tumor tissue biorepository, James Vredenburgh, Core Director; and an Administrative Core, Darell Bigner, Core Director.

描述（由申请人提供）：这是一组资深科学家和医生/科学家向NCI提交的申请，他们具有长期合作历史，提出了治疗神经肿瘤学中两种最难治疗的疾病的新方法，即肿瘤性脑膜炎（NM）和多形性胶质母细胞瘤（GBM）。NM的特征是恶性肿瘤细胞在软脑膜间隙内的扩散和转移性扩散通过脑脊液沿着脑和脊柱。来自乳腺癌和肺癌的NM是最常见的亚型。NM预后差，中位生存期2 ~ 6个月。目前的治疗是无效的，并受到CNS毒性的限制。GBM是最常见和最恶性的原发性脑肿瘤。尽管进行了数百项临床试验，但在过去十年中，只有两种药物，替莫唑胺和贝伐单抗被FDA批准用于治疗。接受这两种药物治疗的患者中不到一半有反应。治疗后复发几乎是普遍的，中位生存期为15至18个月，长期生存者很少。在项目1和3中提出了用配备有Astatine 211或假单胞菌外毒素的单克隆抗体（MAb）或其片段进行靶向免疫治疗以治疗NM或GBM。在项目2中，针对GBM中来自CMV的普遍存在的抗原的疫苗方法被提议通过在替莫唑胺诱导的淋巴细胞减少症的情况下通过施用与IL-2 Ra受体反应的特异性人源化MAb来减少免疫抑制调节性T细胞或TReg来改进。项目1由Michael Zaiutsky领导，名为“使用α粒子发射标记的单克隆抗体进行肿瘤性脑膜炎的靶向放射治疗”。项目2由John Sampson领导，题为“靶向免疫抑制途径以增强脑肿瘤免疫治疗”。项目3，由Darell Bigner领导，标题为“EGFRwt和EGFRvIII双重特异性免疫毒素用于多形性胶质母细胞瘤”。“这三个项目将得到成像核心，核心主任丹尼尔巴博里亚克;生物统计学，信息学，免疫监测和脑肿瘤组织生物储存库的临床支持核心，核心主任詹姆斯Vredenburgh;和行政核心，达雷尔比格纳，核心主任。