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师/科学家向NCI提出的一份申请，他们具有长期合作的历史，他们提出了治疗神经肿瘤学中最难治疗的两种疾病的新方法，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脑脊膜间隙内播散，并沿脑和脊柱通过脑脊液转移扩散。来自乳腺癌和肺癌的NM是最常见的亚型。恶性肿瘤预后严峻，中位生存期为2 ~ 6个月。目前的治疗是无效的，而且对中枢神经系统的毒性有限。GBM是最常见、最恶性的原发性脑肿瘤。尽管进行了数百次临床试验，但在过去十年中，只有替莫唑胺和贝伐单抗两种药物被FDA批准用于治疗。在接受这两种药物治疗的患者中，只有不到一半的人有反应。治疗后复发几乎是普遍的，中位生存期为15至18个月，很少有长期幸存者。项目1和项目3提出了用单克隆抗体（mab）或其片段武装Astatine 211或假单胞菌外毒素用于治疗NM或GBM的靶向免疫治疗。在项目2中，针对CMV在GBM中普遍存在的抗原的疫苗方法被提出，通过使用与IL-2Ra受体反应的特异性人源单抗，在替莫唑胺诱导淋巴细胞减少的情况下，通过降低免疫抑制性调节性t细胞或TReg，来改善疫苗方法。项目1由Michael Zaiutsky领导，名为“使用α粒子发射At标记的单克隆抗体靶向治疗肿瘤性脑膜炎”。项目2由John Sampson领导，名为“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，名为“多形性胶质母细胞瘤的EGFRwt和egfrll双特异性免疫毒素”。这三个项目将由Imaging Core， Core主任Daniel Barboriak；生物统计学、信息学、免疫监测和脑肿瘤组织生物库的临床支持核心，核心主任James Vredenburgh；行政核心，Darell Bigner，核心董事。