Engineered and Encapsulated Stem Cells for Resected Brain Tumors

用于切除脑肿瘤的工程化和封装干细胞

基本信息

批准号：
10578780
负责人：
Khalid A Shah
金额：
$ 36.39万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578780
关键词：
Adult Aftercare Boston Brain Neoplasms CD8-Positive T-Lymphocytes Cancer Patient Cell Cycle Arrest Cell Death Cell Surface Receptors Cells Cessation of life Clinical Clinical Engineering Clinical Research Collaborations Data Encapsulated Engineering Ensure Excision Extracellular Matrix Generations Genetic Genetic Engineering Glioblastoma Goals Human Human Engineering Immune Immune Evasion Immune response Immunohistochemistry Immunotherapy Infiltration Injection of therapeutic agent Interferon-beta Laboratories Ligands Magnetic Resonance Malignant Neoplasms Malignant neoplasm of brain Mediating Mesenchymal Stem Cells Modality Modeling Monoclonal Antibodies Mus Myeloid-derived suppressor cells Nature Operative Surgical Procedures PTEN gene Patients Phenotype Play Positron-Emission Tomography Primary Brain Neoplasms Primary Neoplasm Prognosis Proteins Publishing Resected Role Safety Simplexvirus Surgically-Created Resection Cavity Testing Therapeutic Thymidine Kinase Time Translating Treatment Efficacy Tumor Debulking Tumor Suppressor Proteins Up-Regulation adult stem cell bioluminescence imaging cancer type clinical care clinical translation cytotoxic design engineered stem cells fluorescence imaging imaging biomarker immune cell infiltrate immune checkpoint blockade immune modulating agents immune resistance immunomodulatory therapies immunoregulation in vivo mouse model mutant neoplastic cell neuropathology post-transplant prevent programmed cell death protein 1 programs receptor recruit stem cell fate stem cells time of flight mass spectrometry tumor tumor microenvironment tumor-immune system interactions two photon microscopy

Adult Aftercare Boston Brain Neoplasms CD8-Positive T-Lymphocytes Cancer Patient Cell Cycle Arrest Cell Death Cell Surface Receptors Cells Cessation of life Clinical Clinical Engineering Clinical Research Collaborations Data Encapsulated Engineering Ensure Excision Extracellular Matrix Generations Genetic Genetic Engineering Glioblastoma Goals Human Human Engineering Immune Immune Evasion Immune response Immunohistochemistry Immunotherapy Infiltration Injection of therapeutic agent Interferon-beta Laboratories Ligands Magnetic Resonance Malignant Neoplasms Malignant neoplasm of brain Mediating Mesenchymal Stem Cells Modality Modeling Monoclonal Antibodies Mus Myeloid-derived suppressor cells Nature Operative Surgical Procedures PTEN gene Patients Phenotype Play Positron-Emission Tomography Primary Brain Neoplasms Primary Neoplasm Prognosis Proteins Publishing Resected Role Safety Simplexvirus Surgically-Created Resection Cavity Testing Therapeutic Thymidine Kinase Time Translating Treatment Efficacy Tumor Debulking Tumor Suppressor Proteins Up-Regulation adult stem cell bioluminescence imaging cancer type clinical care clinical translation cytotoxic design engineered stem cells fluorescence imaging imaging biomarker immune cell infiltrate immune checkpoint blockade immune modulating agents immune resistance immunomodulatory therapies immunoregulation in vivo mouse model mutant neoplastic cell neuropathology post-transplant prevent programmed cell death protein 1 programs receptor recruit stem cell fate stem cells time of flight mass spectrometry tumor tumor microenvironment tumor-immune system interactions two photon microscopy

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项目摘要

SUMMARY Glioblastoma (GBM) is the most common primary brain tumor in adults with a very poor prognosis. Given, the central role tumor resection plays in GBM therapy clinical care, understanding the specific influence of tumor resection on immune response in the tumor microenvironment offers a new platform for developing effective immune based therapies for GBM. We have recently developed syngeneic orthotopic mouse GBM-model of tumor resection and shown that tumor debulking results in substantial reduction of myeloid-derived suppressor cells (MDSCs) and simultaneous recruitment of CD4/CD8 T cells into the resection cavity. In this proposal, we will first generate GBM resection models from genetically distinct currently available mouse GBM lines and analyze profiles of immune cells infiltrated into tumor microenvironment pre- and post-tumor debulking. While resection of primary tumor has shown clinical benefit, systemically delivered or direct injection of therapeutic agents in tumor resection cavities has provided limited additional benefit. In our previous studies, we have extensively demonstrated that locally delivered receptor targeted engineered adult stem cells have therapeutic benefits and synthetic extracellular matrix (sECM) encapsulation of stem cells is necessary to prevent their rapid “wash- out” post-transplantation in mouse GBM tumor resection cavity. In our recently published studies, we have shown that sECM encapsulated mesenchymal stem cell (MSC) mediated local delivery of bifunctional, immunomodulatory and cytotoxic protein, interferon (IFN) β enhances selective post-surgical infiltration of CD8 T cells and directly induces cell-cycle arrest in tumor cells. However, IFNβ has been known to upregulate program cell death ligand 1 (PD-L1) expression on tumor cells, thus hindering the immunomodulatory function of IFNβ. Based on the recent findings that: blocking PD-L1 induced by IFNβ treatment eradicates established tumors; tumor suppressor, phosphatase and tensin homolog (PTEN) loss promotes immune resistance; and our exciting preliminary data on: MSC-IFNβ mediated upregulation of PD-L1 in vivo; and local delivery of ScFv-PDL1, we will create bimodal MSC expressing ScFv-PDL1 and IFNβ and test them in syngeneic PTEN wild type (wt.) and mutant GBM models of resection. To ease clinical translation and ensure safety of our approach, we will ultimately engineer clinical grade human MSC to co-express ScFv-PDL1/IFN β and HSV-thymidine kinase (TK) and test our approach in GBM tumors generated from patient derived GBM lines in humanized NSG mice. The incorporation of genetically engineered imaging markers markers into MSC and GBMs will allow us to follow MSC fate and efficacy in vivo and thus to fine tune the proposed approaches. The overall goal of this proposal is thus to immune profile genetically distinct GBM resection models and to assess rationale based therapeutic efficacy of immunomodulatory agents. 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 encapsulated bimodal MSC will be introduced to enhance tumor cell eradication. This will have a major impact in saving the lives of brain cancer patients.

概括胶质母细胞瘤（GBM）是预后较差的成年人中最常见的原发性脑肿瘤。鉴于中心作用肿瘤切除在GBM治疗临床护理中的作用，了解肿瘤的特定影响肿瘤微环境中有关免疫响应的切除提供了一个新的平台，以发展有效 GBM的免疫疗法。我们最近开发了合成的原位小鼠GBM模型肿瘤切除并表明肿瘤缓解导致髓样衍生的抑制大大减少细胞（MDSC）和CD4/CD8 T细胞简单募集到切除腔中。在这个建议中，我们将首先从遗传上不同的鼠标GBM线和分析被浸入肿瘤微环境前后肿瘤后和肿瘤后延伸的免疫细胞的谱。尽管原发性肿瘤的切除已显示出临床益处，全身递送或直接注射治疗肿瘤切除腔的特工提供了有限的额外好处。在我们以前的研究中，我们有广泛证明了本地传递的受体靶向工程成年干细胞的治疗益处和合成的细胞外基质（SECM）的干细胞封装是必要的，以防止其快速小鼠GBM肿瘤切除腔中移植后的“洗涤”。在我们最近发表的研究中，我们已表明SECM封装了间充质干细胞（MSC）介导的双功能，免疫调节和细胞毒性蛋白，干扰素（IFN）β增强了CD8 T的选择性后手术后浸润细胞并直接诱导细胞周期停滞在肿瘤细胞中。但是，已知IFNβ更新程序细胞死亡配体1（PD-L1）在肿瘤细胞上的表达，从而阻碍IFNβ的免疫调节功能。基于最近的发现，即IFNβ处理诱导的pD-L1 radiodicatientic radiodicatienceS已建立的肿瘤；肿瘤抑制剂，磷酸酶和伸长蛋白同源物（PTEN）损失可促进免疫抵抗力；和我们的激动人心初步数据：MSC-IFNβ介导的体内PD-L1的上调；以及SCFV-PDL1的本地交付，我们将创建表达SCFV-PDL1和IFNβ的双峰MSC，并在合成性PTEN野生型（wt。）和突变的GBM切除模型。为了简化临床翻译并确保我们的方法安全，我们将最终，工程师临床级人类MSC至共表达SCFV-PDL1/IFNβ和HSV-胸苷激酶（TK）并测试我们在人源性NSG小鼠中由患者衍生的GBM系产生的GBM肿瘤的方法。这将一般的工程成像标记标记纳入MSC和GBMS将允许我们遵循 MSC的命运和体内效率，从而微调所提出的方法。该提议的总体目标是因此，对于一般不同的GBM切除模型的免疫学概况并评估基于理由的治疗免疫调节剂的功效。一旦得到验证，我们将启动一项临床研究，在大脑时肿瘤手术，主要肿瘤质量将被去除，并将封装的双峰MSC引入增强肿瘤细胞辐射。这将对挽救脑癌患者的生命产生重大影响。