Bone Marrow Stem Cells: Novel Treatment of Human Glioma

骨髓干细胞：人类神经胶质瘤的新疗法

• 批准号: 7883423
• 负责人: FREDERICK F LANG
• 金额: $ 26.54万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-26 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883423
• 关键词: Address; Animal Disease Models; Applications Grants; Autologous Stem Cell Transplantation; Autologous Transplantation; Behavior; Biological; Biological Products; Biological Response Modifier Therapy; Bioluminescence; Blood; Bone Marrow; Bone Marrow Stem Cell; Brain; Brain Neoplasms; Clinic; Clinical; Data; Databases; Disease; EGF gene; Engineering; Engraftment; Female; Genes; Glioma; Goals; Growth Factor; Human; Human Biology; Human Engineering; Image; Immunocompetent; In Vitro; Individual; Interferon-beta; Interferons; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Mediating; Mesenchymal Stem Cells; Methods; Modeling; Mus; Organ; Patients; Peripheral; Principal Investigator; Proliferating; Property; Role; Safety; Series; Stem cells; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Toxic effect; Translating; Transplantation; Tropism; Tumor-Derived; Viral Genes; Xenograft procedure; base; cancer therapy; cellular engineering; chemokine; effective therapy; improved; in vivo; male; mouse model; neoplastic cell; neutralizing antibody; novel; platelet-derived growth factor BB; programs; self-renewal; sex; therapeutic gene; therapeutic protein; tumor; Address; Animal Disease Models; Applications Grants; Autologous Stem Cell Transplantation; Autologous Transplantation; Behavior; Biological; Biological Products; Biological Response Modifier Therapy; Bioluminescence; Blood; Bone Marrow; Bone Marrow Stem Cell; Brain; Brain Neoplasms; Clinic; Clinical; Data; Databases; Disease; EGF gene; Engineering; Engraftment; Female; Genes; Glioma; Goals; Growth Factor; Human; Human Biology; Human Engineering; Image; Immunocompetent; In Vitro; Individual; Interferon-beta; Interferons; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Mediating; Mesenchymal Stem Cells; Methods; Modeling; Mus; Organ; Patients; Peripheral; Principal Investigator; Proliferating; Property; Role; Safety; Series; Stem cells; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Time; Toxic effect; Translating; Transplantation; Tropism; Tumor-Derived; Viral Genes; Xenograft procedure; base; cancer therapy; cellular engineering; chemokine; effective therapy; improved; in vivo; male; mouse model; neoplastic cell; neutralizing antibody; novel; platelet-derived growth factor BB; programs; self-renewal; sex; therapeutic gene; therapeutic protein; tumor

DESCRIPTION (provided by applicant): Successful treatment of human glioma, the most deadly brain tumor, has not been achieved in large part because of deficiencies in current delivery strategies. To improve delivery, we have exploited the unique properties of bone marrow-derived, human mesenchymal stem cells (hMSCs) to overcome the deficiencies of current delivery methods. We have shown that hMSCs localize to gliomas after systemic and local administration. Mouse MSCs (mMSCs) behave similarly in syngeneic models that mimic transplant into immunocompetent subjects. Other studies show that tumor-derived factors, particularly PDGF-BB, may mediate the tropism hMSCs have for gliomas. Importantly, we have also demonstrated that hMSCs engineered to release interferon-beta (IFN-beta) have powerful anti-glioma effects in an animal model of this disease. On the basis of these data, we hypothesize that human bone marrow-derived mesenchymal stem cells can be used as delivery vehicles for treatment of gliomas and that hMSCs engineered to release IFN-beta are effective anti-glioma agents. To help achieve our long-term goal of applying this approach to patients, we propose a series of studies that are expected to provide fundamental biological information necessary for translating this investigational approach to patients. Thus, to test our hypothesis, we will determine the survival, proliferation, and differentiation of hMSCs within and outside gliomas by tracking donor hMSCs in sex mismatched recipient glioma intracranial xenografts; non-invasive imaging will also be used to follow in real time the fate of systemically administered hMSCs in individual subjects. Additionally, to better mimic autologous transplantation, the capacity of mMSCs to survive within and outside gliomas will be explored in syngeneic, immunocompetent mice (Aim 1). To evaluate the mechanisms underlying the tropism of hMSCs for gliomas, we will define the extent to which specific tumor-derived factors, identified during preliminary in vitro studies, contribute to the attraction of hMSCs for glioma in vivo (Aim 2). Lastly, the efficacy and toxicity of IFN-beta-engineered MSCs will be analyzed in xenograft intracranial models of human glioma and in immunocompetent syngeneic mouse model; measurements of intratumoral and systemic IFN-beta levels will define the extent to which hMSC-delivery improves the therapeutic index of IFN-beta (Aim 3). Successful use of hMSCs to deliver therapeutic proteins to brain tumors will represent a major step forward in enhancing treatments of patients with this deadly disease for whom only minimally-effective therapies are currently available.

描述（由申请人提供）：成功治疗人神经胶质瘤，是最致命的脑肿瘤，在很大程度上并没有达到当前递送策略的不足。为了改善递送，我们利用了骨髓衍生的人间充质干细胞（HMSC）的独特特性，以克服当前递送方法的缺陷。我们已经表明，HMSC在全身和局部给药后将其定位于神经胶质瘤。小鼠MSC（MMSC）在模仿移植到免疫功能受试者的合成模型中表现类似。其他研究表明，肿瘤衍生的因素，尤其是PDGF-BB，可能介导了HMSC的胶质瘤。重要的是，我们还证明了设计用于释放干扰素β（IFN-BETA）的HMSC在该疾病的动物模型中具有强大的抗脱光瘤作用。根据这些数据，我们假设人骨髓衍生的间充质干细胞可用作送货车进行治疗，以治疗神经胶质瘤，并且设计用于释放IFN-BETA的HMSC是有效的抗胶质瘤药物。为了帮助实现将这种方法应用于患者的长期目标，我们提出了一系列研究，这些研究有望提供将这种研究方法转化为患者所需的基本生物学信息。因此，为了检验我们的假设，我们将通过跟踪性不匹配的受体神经瘤内颅内异种移植物中的供体HMSC来确定HMSC内外HMSC的生存，增殖和分化；非侵入性成像也将用于实时遵循各个受试者中系统管理的HMSC的命运。此外，为了更好地模拟自体移植，将在同步，免疫能力的小鼠中探索MMSC在神经胶质瘤内外生存的能力（AIM 1）。为了评估HMSC对神经胶质瘤的偏见的基础机制，我们将定义在初步体外研究期间确定的特定肿瘤衍生因子的程度，有助于吸引HMSC对体内神经胶质瘤的吸引力（AIM 2）。最后，将在人神经胶质瘤的异种移植颅内模型和免疫能力的同性小鼠模型中分析IFN-β工程MSC的功效和毒性。肿瘤内和全身IFN-β水平的测量将定义HMSC递送改善IFN-BETA的治疗指数的程度（AIM 3）。成功使用HMSC将治疗蛋白传递给脑肿瘤将是增强这种致命疾病患者治疗的主要一步，而这种疾病目前只有最低效率的疗法。