Concurrent Immune Stimulation and Inhibition of Angiogenesis for Glioma Therapy

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，通常在常规治疗后两年内死亡，包括手术、放疗和化疗。最近的研究表明，罕见的CD133+脑瘤干细胞(BTSCs)可能是导致治疗抵抗和脑肿瘤复发的原因。因此，应开发针对BTSCs的新疗法。BTSC被发现依赖血管周围的利基来维持自我更新，这使得抗血管生成治疗成为与BTSC靶向细胞毒治疗相结合的基本佐剂。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反应，但这通常并不是治愈的。我们推测，抗血管生成基因治疗与BTSC靶向树突状细胞疫苗的结合将为根除小鼠GBM提供协同和优越的抗肿瘤效果。为了验证这一假设，该项目需要开发一种名为睡美人(SB)的新型非病毒载体用于抗血管生成基因转移，以及一种创新的富含BTSC的树突状细胞疫苗用于针对BTSCs的免疫治疗。在特定的目的1中，我们将确定SB介导的抗血管生成基因治疗对BTSC在体外和体内的存活和效力的影响。在特定目标2中，将比较富含BTSC的裂解物冲击的树突状细胞疫苗和亲本细胞裂解物冲击的疫苗在荷脑胶质瘤的小鼠中的抗肿瘤效果。在具体目标3中，最有效的抗血管生成基因治疗将与最有效的免疫治疗相结合，以确定是否达到协同抗肿瘤效果。该项目具有很高的影响潜力，因为我们可能会找到一种有效且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，并评估这些疗法的联合疗效。这些研究将提供有关使用这些新方法治疗基底膜患者的可行性的信息。相关声明胶质母细胞瘤是一种致命的脑瘤，仅在美国每年就导致近1.3万人死亡。在这个项目中，我们将开发和测试一种联合基因治疗/免疫治疗的方法来治疗小鼠胶质母细胞瘤。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找到一种新的治疗方法。

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.