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: 8917131
• 负责人: DARELL D BIGNER
• 金额: $ 369.83万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917131
• 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; Physicians; Positron-Emission Tomography; Primary Brain Neoplasms; Pseudomonas; Radioactivity; Radioimmunotherapy; Radioisotopes; Radiometry; Radiopharmaceuticals; 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 radiation; dehalogenation; design; effective therapy; improved; lung Carcinoma; meetings; neoplasm immunotherapy; neoplastic cell; neuro-oncology; novel; novel strategies; outcome forecast; overexpression; panitumumab; phase I trial; phase II trial; 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）：这是一组具有长期合作历史的资深科学家和医生/科学家向 NCI 提交的申请，他们提出了治疗神经肿瘤学中最难治的两种疾病的新方法，即肿瘤性脑膜炎 (NM) 和多形性胶质母细胞瘤 (GBM)。 NM 的特点是恶性肿瘤细胞在软脑膜间隙内播散，并通过脑脊液沿着大脑和脊柱进行转移扩散。乳腺癌和肺癌的 NM 是最常见的亚型。 NM 的预后很严峻，中位生存期为 2 至 6 个月。目前的治疗无效并且受到中枢神经系统毒性的限制。 GBM 是最常见、恶性程度最高的原发性脑肿瘤。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。用这两种药物治疗的患者中只有不到一半有反应。治疗后复发几乎是普遍现象，中位生存期为 15 至 18 个月，长期生存者很少。项目 1 和项目 3 提出了使用带有砹 211 或假单胞菌外毒素的单克隆抗体 (MAb) 或其片段的靶向免疫疗法来治疗 NM 或 GBM。在项目 2 中，建议通过减少 GBM 中的免疫抑制调节性 T 细胞或 TReg 来改进针对 GBM 中 CMV 普遍存在的抗原的疫苗方法。 通过施用与 IL-2Ra 受体反应的特定人源化 MAb 来设置替莫唑胺诱导的淋巴细胞减少症。项目 1 由 Michael Zaiutsky 领导，题为“使用标有 Alpha 粒子发射 At 的单克隆抗体对肿瘤性脑膜炎进行靶向放射治疗”。项目 2 由 John Sampson 领导，标题为“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“针对多形性胶质母细胞瘤的 EGFRwt 和 EGFRvlll 双特异性免疫毒素”。这三个项目将得到成像核心、核心总监 Daniel Barboriak 的支持；生物统计学、信息学、免疫监测和脑肿瘤组织生物样本库的临床支持核心，核心主任 James Vredenburgh；行政核心：Darell Bigner，核心总监。