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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：
7490563
负责人：
John R Ohlfest
金额：
$ 16.35万
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/7490563
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）：