Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors

描述(由申请人提供)：这是一组有长期合作历史的资深科学家和内科医生/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疗的两种疾病-肿瘤性脑膜炎(NM)和多形性胶质母细胞瘤(GBM)-的新方法。NM的特点是恶性肿瘤细胞在软脑膜间隙内扩散，并通过脑脊液沿大脑和脊柱转移。乳腺癌和肺癌的NM是最常见的亚型。NM预后较差，中位生存期为2~6个月。目前的治疗方法是无效的，而且受到中枢神经系统毒性的限制。基底节细胞瘤是最常见、最恶性的原发脑肿瘤。尽管进行了数百次临床试验，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。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。在项目1和项目3中，建议使用单抗或其片段与他汀类211或假单胞菌外毒素一起靶向免疫治疗NM或GBM。在项目2中，针对GBM中普遍存在的CMV抗原的疫苗方法被建议通过在替莫唑胺诱导的淋巴细胞减少症中减少免疫抑制调节性T细胞或Treg来改进，方法是注射与IL-2ra受体反应的特异性人源化MAb。项目1由Michael Zaiutsky领导，题为“使用标记有阿尔法粒子发射的单抗进行肿瘤脑膜炎的靶向放射治疗”。项目2由John Sampson领导，名为“定向免疫抑制途径以加强脑瘤免疫治疗”。项目3由Darell Bigner领导，名为“EGFRUT和EGFRv11双特异性免疫毒素治疗多形性胶质母细胞瘤”。这三个项目将由核心董事Daniel Barboriak的成像核心、核心董事James Vredenburgh和核心董事Darell Bigner支持的生物统计、信息学、免疫监测和脑瘤组织生物仓库的临床支持核心提供支持。

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.