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BMP4 Engineered Mesenchymal Stem Cell Therapy for Glioblastoma

BMP4 工程间充质干细胞治疗胶质母细胞瘤

基本信息

批准号：
9188284
负责人：
ALFREDO QUINONES-HINOJOSA
金额：
$ 13.8万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-08 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188284
关键词：
Accounting Adherence Adipose tissue Adjuvant Radiotherapy Adult Affect Age Allogenic Animals Antineoplastic Agents Apoptosis Autologous Blood - brain barrier anatomy Bone Marrow Brain Brain Neoplasms Cells Characteristics Clinical Clinical Trials Devices Effectiveness Endothelium Engineering Excision Future Glioblastoma Glioma Goals Grant Health Human Immune Immunotherapeutic agent In Vitro Invaded Investigation Lead Local Therapy Longevity Malignant Neoplasms Malignant neoplasm of brain Mesenchymal Stem Cells Microfluidics Modeling Morbidity - disease rate Mus Nature Oncogenic Operative Surgical Procedures Patients Plague Primary Brain Neoplasms Proteins Radiation Radiation therapy Radio Reaction Recurrence Research Research Design Resistance Safety Source Stem cells Surface Survival Rate Targeted Radiotherapy Techniques Testing Therapeutic Therapeutic Effect Translating Tropism Tumor Burden Tumor Escape Viral Xenograft Model bone morphogenic protein brain parenchyma cancer cell cancer type cell motility cellular engineering chemoradiation clinical application effective therapy genetically modified cells implantation in vivo in vivo Model ineffective therapies migration mortality mouse model nanobiotechnology neoplastic cell novel novel therapeutics research study response stem cell therapy targeted delivery treatment strategy tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Glioblastoma (GBM) is the most common primary brain tumor in adults, and accounts for 20% of all primary brain tumors. GBM has a median survival rate of only 14.6 months despite current best treatment practices which include surgery and chemoradiation. A significant reason for this morbidity and mortality is the ability of GBM to invade normal brain parenchyma, making localized treatment ineffective. In order for treatment to be effective, these invading cells need to be targeted. One promising approach involves the use of mesenchymal stem cells (MSCs), which have been found by our group and by others to migrate preferentially to cancer cells. Moreover, MSCs can be engineered to synthesize and release anti-tumor proteins, such as bone morphogenic protein 4 (BMP4), which has been found to affect brain tumor initiating cells (BTICs). MSCs can be obtained from bone marrow (BM-MSC) and adipose tissue (AMSC). The use of BM-MSCs has been limited because these cells are difficult to obtain, have limited ex vivo proliferation capacity, and decrease in effectiveness with increasing donor age. AMSCs may therefore be a better option. In this grant, we propose to use a novel source for human MSCs, adipose tissue from our patients, and genetically modify these cells to secrete BMP4 for the treatment of GBM. In contrast to BM-MSCs, human AMSCs (hAMSCs) provide a therapeutically comparable source of cells which are more readily accessible and have better ex vivo expansibility. Our overall hypothesis is that virally-modified hAMSCs expressing BMP4 in combination with adjuvant radiotherapy constitute an effective treatment against intracranial GBM. To achieve these goals, we will pursue the following specific aims: (Aim 1) To determine the tumor tropism, endothelial adherence, blood brain barrier crossing capability, and anti-glioma response of virally-modified BMP4-secreting primary hAMSCs in vitro-we have shown this with commercial hAMSCs and we propose to do it now with Freshly extracted Adipose Tissue (F.A.T.); (Aim 2) To determine the safety and efficacy of virally-modified BMP4-secreting hAMSCs in combination with targeted radiation therapy on human GBM in an in vivo murine model. The techniques to be used in vitro and in vivo in this proposal have been developed and further characterized by our team and by our collaborators. In vitro studies will be conducted using new advancements in the fields of microfluidics and nanobiotechnology. In vivo studies will employ a mammalian xenograft model that engrafts human BTIC- derived GBM, which bests recapitulates human GBM. Additionally, we will use the small animal radiation research platform (SARRP), a novel device developed and used by our team and collaborators, which allows the delivery of targeted beams of radiation therapy to tumor-bearing mice analogous to confocal beam therapy in humans. The SARRP is capable of focusing a beam of radiation with an accuracy of 0.2 mm, recreating radiotherapy for humans on the scale of a mouse. In addition to our experiments on commercial hAMSCs, we will obtain primary hAMSCs intraoperatively from human patients and test their anti-tumor efficacy to maximize the clinical translatability of this study. The results of this stuy will demonstrate whether hAMSCs can provide a treatment that is safe and effective for not only patients with GBM, but many types of primary and metastatic brain cancers. The results of this study may likely lead to clinical trials, with a revolutionary new way of treating patients with brin cancer.

描述（由申请人提供）：胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤，占所有原发性脑肿瘤的20%。尽管目前的最佳治疗方法包括手术和放化疗，GBM 的中位生存率仅为 14.6 个月。这种发病率和死亡率的一个重要原因是 GBM 能够侵入正常脑实质，导致局部治疗无效。为了使治疗有效，需要针对这些入侵细胞。一种有前途的方法涉及使用间充质干细胞（MSC），我们的团队和其他人发现这种细胞优先迁移到癌细胞。此外，间充质干细胞可以被改造为合成和释放抗肿瘤蛋白，例如骨形态发生蛋白4（BMP4），它被发现会影响脑肿瘤起始细胞（BTIC）。 MSC 可以从骨髓 (BM-MSC) 和脂肪组织 (AMSC) 中获得。 BM-MSC 的使用受到限制，因为这些细胞难以获得，离体增殖能力有限，并且随着供体年龄的增加其有效性降低。因此，AMSC 可能是更好的选择。在这笔资助中，我们建议使用人类 MSC（来自患者的脂肪组织）的新来源，并对这些细胞进行基因改造，使其分泌 BMP4 来治疗 GBM。与 BM-MSC 相比，人 AMSC (hAMSC) 提供了治疗上可比的细胞来源，更容易获得且具有更好的离体扩展性。我们的总体假设是，表达 BMP4 的病毒修饰 hAMSC 与辅助放疗相结合，构成了针对颅内 GBM 的有效治疗方法。为了实现这些目标，我们将追求以下具体目标：（目标1）确定病毒修饰的BMP4分泌原代hAMSC的体外肿瘤趋向性、内皮粘附性、血脑屏障穿越能力和抗神经胶质瘤反应——我们已经用商业hAMSC证明了这一点，我们建议现在用新鲜提取的脂肪组织（F.A.T.）进行此操作；（目标 2）确定病毒修饰的 BMP4 分泌 hAMSC 与靶向放射治疗相结合，在体内小鼠模型中对人 GBM 的安全性和有效性。本提案中使用的体外和体内技术已由我们的团队和合作者开发并进一步表征。将利用微流体和纳米生物技术领域的新进展进行体外研究。体内研究将采用哺乳动物异种移植模型，该模型植入人类 BTIC 衍生的 GBM，这最好地再现了人类 GBM。此外，我们将使用小动物放射研究平台（SARRP），这是我们团队和合作者开发和使用的一种新型设备，它可以向荷瘤小鼠提供靶向放射治疗光束，类似于人类的共焦光束治疗。 SARRP 能够以 0.2 毫米的精度聚焦辐射束，以小鼠的规模重现人类放射治疗。除了我们对商业 hAMSC 进行的实验外，我们还将在术中从人类患者身上获取原代 hAMSC，并测试其抗肿瘤功效，以最大限度地提高本研究的临床可转化性。这项研究的结果将证明 hAMSC 是否不仅可以为 GBM 患者提供安全有效的治疗，还可以为多种类型的原发性和转移性脑癌提供安全有效的治疗。这项研究的结果可能会导致临床试验，为治疗布林癌患者提供革命性的新方法。