In vivo imaging of encapsulated stem cells in mouse models of tumor resection

肿瘤切除小鼠模型中封装干细胞的体内成像

基本信息

批准号：
8421265
负责人：
Khalid A Shah
金额：
$ 33.47万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8421265
关键词：
Adjuvant Adjuvant Chemotherapy Adult Aminolevulinic Acid Apoptosis Boston Brain Brain Neoplasms Cancer Patient Carmustine Cell Survival Cells Clinical Clinical Research Collaborations Deposition Development Disease Drug Kinetics Encapsulated Engineering Ensure Epidermal Growth Factor Receptor Excision Extracellular Matrix Fluorescence Fluorescent Dyes Future Genetic Engineering Glioblastoma Glioma Goals Home environment Homing Human Human Engineering Image In Vitro Injection of therapeutic agent Invaded Laboratories Lead Ligands Magnetic Resonance Imaging Malignant - descriptor Malignant neoplasm of brain Mesenchymal Stem Cells Microscopy Modeling Mus Nature Operative Surgical Procedures Optics Pathology Patients Phenotype Play Positron-Emission Tomography Primary Brain Neoplasms Primary Neoplasm Progression-Free Survivals Publishing Radiation therapy Recurrence Research Personnel Resected Residual state Resistance Role Safety Simplexvirus Simulate Site Solid Stem cells Surgically-Created Resection Cavity TNFSF10 gene Testing Therapeutic Thymidine Kinase Time Transplantation Treatment Efficacy Tumor Debulking Tumor Necrosis Factor-alpha Tumor Volume Universities Utah Virus antitumor agent base cell killing cell motility cell suicide cellular engineering chemotherapeutic agent design in vivo intravital microscopy killings mortality mouse model nanobodies neoplastic cell novel outcome forecast preclinical study prevent public health relevance standard care suicide gene therapeutic protein tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The standard treatment for malignant glioblastoma multiforme (GBM) includes maximal surgical tumor resection followed by radiation therapy and adjuvant chemotherapy. However, recurrence rates of GBM and the associated patient mortality are nearly 100%. Despite the key role of tumor resection in clinical GBM therapy, most of the pre-clinical studies focus on treating solid intact intracranial GBM tumors without mimicking the clinical scenario of surgical resection. Therefore, implementation of tumor resection in mouse models that recapitulate the clinical disease features are critical in developing clinically translatable therapies for GBM. In the proposed studies, we will first create and characterize different GBM resection models using patient derived CD133+ GBMs based on 3 different phenotypes (invasive, semi-invasive and nodular). While resection of primary tumor has shown clinical benefit, systemically delivered chemotherapeutic agents or direct injection of viruses and placement of carmustine (BCNU) wafers in tumor resection cavities has provided very limited additional benefit. Based on our recent findings that encapsulation of mesenchymal stem cells (MSC) is necessary to prevent rapid "wash- out" of stem cells post-transplantation in the tumor resection cavity, we will encapsulate human MSC engineered to express in vitro and in vivo imaging markers into synthetic extracellular matrices (sECMs) and evaluate them for their retention, survival and tumor homing in mouse resection models of GBM with different phenotypes. Based on our preliminary studies which indicate that a novel anti-tumor agent consisting of a secretable version of epidermal growth factor receptor targeted nanobody fused to tumor necrosis factor apoptosis inducing ligand (Enb-TRAIL), induces GBM cell killing in both TRAIL resistant and sensitive GBMs, encapsulated MSC-Enb- TRAIL will be tested in different GBM models of resection. To ensure the safety of our approach, we will ultimately engineer human MSC-Enb-TRAIL to express HSV-thymidine kinase (TK), an activatable cellular suicide gene that will allow us to selectively eradicate MSC post-GBM treatment. The incorporation of genetically engineered fluorescent and bioluminescent imaging (BLI) markers into MSC and GBMs will allow us to follow GBM cell invasion, fate of MSC and pharmacokinetics of therapeutic proteins and their efficacy by in vivo BLI, intravital microscopy (IVM), magnetic resonance imaging (MRI) and positron emission tomography (PET) and thus to fine tune the proposed approaches. Once validated, we will initiate a clinical study in which at the time of brain tumor surgery, the main tumor mass will be removed and sECMs encapsulated MSC will be introduced to target a broad spectrum of remaining tumor cells and micro-invasive tumor deposits in the brain. This will have a major impact in saving the lives of many brain cancer patients.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）的标准治疗方法包括最大手术肿瘤切除，然后进行放射治疗和辅助化疗。但是，GBM和相关患者死亡率的复发率接近100％。尽管肿瘤切除在临床GBM治疗中的关键作用，但大多数临床前研究都集中于治疗固体完整的颅内GBM肿瘤，而无需模仿手术切除的临床情况。因此，在概括临床疾病特征的小鼠模型中的肿瘤切除术在开发GBM的临床可翻译疗法中至关重要。在拟议的研究中，我们将使用基于3种不同表型的患者衍生的CD133+ GBM（侵入性，半侵入性和结节性）来创建和表征不同的GBM切除模型。虽然原发性肿瘤的切除已显示出临床益处，但系统地递送化学治疗剂或直接注射病毒和卡莫斯汀（BCNU）晶圆在肿瘤切除腔中的放置提供了非常有限的额外好处。 Based on our recent findings that encapsulation of mesenchymal stem cells (MSC) is necessary to prevent rapid "wash- out" of stem cells post-transplantation in the tumor resection cavity, we will encapsulate human MSC engineered to express in vitro and in vivo imaging markers into synthetic extracellular matrices (sECMs) and evaluate them for their retention, survival and tumor homing in mouse resection models of GBM with different表型。基于我们的初步研究，该研究表明，由可分泌的表皮生长因子受体组成的新型抗肿瘤剂靶向靶向纳米型，融合了与肿瘤坏死因子配体诱导配体（ENB-TRAIL）的凋亡诱导，诱导两种跟踪和敏感的GB gb gb的GBM Cells trable trable trable consected MSC-eNBB-Enbm-Enbm in narly诱导GBM Cell杀死。为了确保我们的方法的安全性，我们最终将设计人类MSC-ENB-Trail以表达HSV-胸腺苷激酶（TK），这是一种可激活的细胞自杀基因，它将使我们能够选择性地消除MSC GBM治疗。将基因工程的荧光和生物发光成像（BLI）标记（BLI）纳入MSC和GBM将使我们能够遵循GBM细胞侵袭，MSC的命运，MSC的命运以及治疗性蛋白质的命运，并在体内（IIVM），TONINE（IVM）和POTIT IMITON（MRI）和POTIT to PROTITS（MRI）和POTITS（MRI）的效率（MRISCOPY BLI）的功效建议的方法。一旦得到验证，我们将启动一项临床研究，在该研究中，在脑肿瘤手术时，将去除主要的肿瘤肿块，并将引入SECMS封装的MSC，以靶向剩余的肿瘤细胞和大脑中剩余的肿瘤细胞和微侵入性肿瘤沉积物。这将对挽救许多脑癌患者的生命产生重大影响。