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

基本信息

批准号：
8724198
负责人：
DARELL D BIGNER
金额：
$ 346.97万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8724198
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

项目摘要

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 提出的申请，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。治疗，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。项目 2 中建议针对 GBM 中普遍存在的 CMV 抗原进行疫苗方法在替莫唑胺诱导的淋巴细胞减少症中，通过给予特定的药物来减少免疫抑制调节性 T 细胞或 TReg 来改善人源化 MAb 与 IL-2Ra 受体发生反应。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。