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Concurrent Immune Stimulation and Inhibition of Angiogenesis for Glioma Therapy

神经胶质瘤治疗中同时免疫刺激和血管生成抑制

基本信息

批准号：
7384288
负责人：
John R Ohlfest
金额：
$ 19.62万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7384288
关键词：
Accounting Address Adjuvant Adult Angiogenesis Inhibition Angiogenic Factor Angiostatins Antigen-Presenting Cells Antigens Blood capillaries Brain Neoplasms CD8B1 gene Cause of Death Cell Survival Cells Clinical Data Clinical Research Combined Modality Therapy Complex Cytotoxic Chemotherapy Dendritic Cell Vaccine Dendritic Cells Development Endostatins Endothelial Cells Epitopes Excision Flow Cytometry Gene Combinations Gene Expression Gene Transfer Glioblastoma Glioma Growth Histology Human Immune Immune response Immune system Immunotherapy In Vitro Interferons Intracranial Neoplasms Invasive Light Mediating Modality Mono-S Mus Operative Surgical Procedures Patients Physiologic pulse Plasmids Prevention Pulse taking Radiation therapy Radiosurgery Recruitment Activity Recurrence Resistance Sleeping Beauty Source T-Lymphocyte Testing Therapeutic Transplantation Tumor Antigens Tumor Stem Cell Assay Tumor Stem Cells Tumor-Derived United States Vaccination Vaccines Vascular blood supply angiogenesis base cancer therapy chemotherapy combination gene therapy fusion gene gene delivery system gene therapy gene transfer vector improved in vivo innovation interest killings mouse model neoplastic cell novel novel strategies outcome forecast pre-clinical response self renewing cell self-renewal tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma Multiforme (GBM) is a lethal brain tumor that typically causes death within two years after conventional therapies consisting of surgery, radiation, and chemotherapy. Recent studies have shown that rare CD133+ brain tumor stem cells (BTSCs) are the likely cause of therapy resistance and brain tumor recurrence. Therefore, novel therapies that target BTSCs should be developed. BTSCs have been found to rely on a perivascular niche to sustain self-renewal, which makes anti- angiogenic therapy a rationale adjuvant to combine with BTSC-targeted cytotoxic therapy. Recent clinical data demonstrates that dendritic cell vaccines can elicit a tumor- reactive immune response in GBM patients, but this has typically not been curative. We hypothesize that the combination of anti-angiogenic gene therapy with a BTSC-targeted dendritic cell vaccine will provide synergistic and superior anti-tumor effects to eradicate murine GBM. To test this hypothesis this project entails the translational development of a novel nonviral vector called Sleeping Beauty (SB) for anti-angiogenic gene transfer, and an innovative BTSC-enriched dendritic cell vaccine for immunotherapy against BTSCs. In Specific Aim 1, we will determine the effects of SB-mediated anti-angiogenic gene therapy on BTSC survival and potency in vitro and in vivo. In Specific Aim 2, the anti-tumor efficacy of a BTSC-enriched, lysate-pulsed dendritic cell vaccine will be compared to a parental cell, lysate-pulsed vaccine in mice bearing intracranial gliomas. In Specific Aim 3, the most effective anti-angiogenic gene therapy will be combined with the most effective immunotherapy in glioma-bearing mice to determine if synergistic anti- tumor efficacy is achieved. This project has high impact potential because we may identify an effective and scalable anti-angiogenic therapy, an immunotherapy capable of killing glioma cells responsible for tumor renewal, and assess the efficacy of the combination of these therapies. Together these studies will provide information regarding the feasibility of using these novel approaches for treating patients with GBM. Statement of Relevance Glioblastoma is a fatal brain tumor that kills nearly 13,000 people every year in the United States alone. In this project we will develop and test a combined gene therapy / immune therapy for the treatment of glioblastoma in mice. The project has high impact potential because it may identify a new treatment approach for glioblastoma patients.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是一种致命的脑肿瘤，通常在手术，放疗和化疗组成的常规治疗后两年内导致死亡。最近的研究表明，罕见的CD 133+脑肿瘤干细胞（BTSC）是治疗抵抗和脑肿瘤复发的可能原因。因此，应该开发靶向BTSC的新疗法。已经发现BTSC依赖于血管周围小生境来维持自我更新，这使得抗血管生成疗法成为联合收割机与BTSC靶向细胞毒性疗法组合的基本辅助疗法。最近的临床数据表明，树突状细胞疫苗可以在GBM患者中引发肿瘤反应性免疫应答，但这通常不是治愈性的。我们假设抗血管生成基因治疗与BTSC靶向树突状细胞疫苗的组合将提供协同和上级抗肿瘤作用以根除小鼠GBM。为了验证这一假设，该项目需要翻译开发一种名为Sleeping Beauty（SB）的新型非病毒载体，用于抗血管生成基因转移，以及一种创新的BTSC富集树突状细胞疫苗，用于针对BTSC的免疫治疗。在具体目标1中，我们将确定SB介导的抗血管生成基因治疗对BTSC存活和体外和体内效力的影响。在具体目标2中，将在携带颅内神经胶质瘤的小鼠中比较BTSC富集的裂解物脉冲的树突状细胞疫苗与亲本细胞裂解物脉冲的疫苗的抗肿瘤功效。在特定目标3中，最有效的抗血管生成基因疗法将与最有效的免疫疗法在荷神经胶质瘤小鼠中组合，以确定是否实现协同抗肿瘤功效。该项目具有很高的影响潜力，因为我们可以确定一种有效和可扩展的抗血管生成疗法，一种能够杀死负责肿瘤更新的胶质瘤细胞的免疫疗法，并评估这些疗法组合的疗效。这些研究将共同提供关于使用这些新方法治疗GBM患者的可行性的信息。胶质母细胞瘤是一种致命的脑肿瘤，仅在美国每年就有近13，000人死亡。在这个项目中，我们将开发和测试用于治疗小鼠胶质母细胞瘤的联合基因疗法/免疫疗法。该项目具有很高的影响潜力，因为它可能为胶质母细胞瘤患者确定一种新的治疗方法。