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

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）是成人中最常见的原发性脑肿瘤，预后非常差。肿瘤切除在 GBM 治疗临床护理中发挥核心作用，了解肿瘤的具体影响肿瘤微环境中免疫反应的切除为开发有效的我们最近开发了 GBM 的同基因原位小鼠 GBM 模型。肿瘤切除并表明肿瘤减灭导致骨髓源性抑制基因大幅减少细胞（MDSC）并同时将 CD4/CD8 T 细胞招募到切除腔中。将首先从遗传上不同的当前可用的小鼠 GBM 系中生成 GBM 切除模型，分析肿瘤减灭前后浸润到肿瘤微环境中的免疫细胞的概况。原发肿瘤切除术已显示出临床益处，全身输送或直接注射治疗剂在我们之前的研究中，肿瘤切除腔中的药物提供了有限的额外益处。普遍证明，局部递送的受体靶向工程成体干细胞具有治疗作用干细胞的好处和合成细胞外基质（sECM）封装对于防止其快速在我们最近发表的研究中，我们在小鼠 GBM 肿瘤切除腔中进行了“冲洗”。研究表明，sECM 封装的间充质干细胞 (MSC) 介导双功能的局部递送，免疫调节和细胞毒性蛋白干扰素 (IFN) β 增强 CD8 T 的选择性术后浸润细胞并直接诱导肿瘤细胞的细胞周期停滞。然而，已知 IFNβ 可以上调程序。肿瘤细胞上细胞死亡配体1（PD-L1）的表达，从而阻碍IFNβ的免疫调节功能。根据最近的研究结果：阻断 IFNβ 治疗诱导的 PD-L1 可根除已形成的肿瘤；肿瘤抑制因子、磷酸酶和张力蛋白同源物 (PTEN) 缺失可促进免疫抵抗；关于以下方面的初步数据：MSC-IFNβ 介导的 PD-L1 体内上调；以及 ScFv-PDL1 的局部递送，我们将创建表达 ScFv-PDL1 和 IFNβ 的双峰 MSC，并在同基因 PTEN 野生型（wt.）中测试它们，为了简化临床转化并确保我们方法的安全性，我们将进行突变 GBM 切除模型。最终设计出临床级人类 MSC 来共表达 ScFv-PDL1/IFN β 和 HSV-胸苷激酶 (TK) 并在人源化 NSG 小鼠中测试由患者来源的 GBM 系产生的 GBM 肿瘤的方法。将基因工程成像标记物纳入 MSC 和 GBM 将使我们能够遵循 MSC 在体内的命运和功效，从而微调所提出的方法该提案的总体目标是。因此，免疫谱具有遗传上不同的 GBM 切除模型，并评估基于治疗的基本原理一旦免疫调节剂的功效得到验证，我们将启动一项临床研究，其中在大脑时。肿瘤手术，主要肿瘤块将被切除，封装的双峰间充质干细胞将被引入加强肿瘤细胞的根除，这将对挽救脑癌患者的生命产生重大影响。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Immune Profiling of Syngeneic Murine and Patient GBMs for Effective Translation of Immunotherapies.

同基因小鼠和患者 GBM 的免疫分析，以实现免疫疗法的有效转化。

DOI：
发表时间：
2021-02-25
期刊：
影响因子：
6
作者：
Khalsa, Jasneet Kaur;Shah, Khalid
通讯作者：
Shah, Khalid

Engineered cell-based therapies in ex vivo ready-made CellDex capsules have therapeutic efficacy in solid tumors.

体外现成的 CellDex 胶囊中基于工程细胞的疗法对实体瘤具有治疗功效。

DOI：
发表时间：
2023-06
期刊：
影响因子：
0
作者：
van Schaik, Thijs A;Moreno;Aligholipour Farzani, Touraj;Wang, Mian;Chen, Kok;Li, Wanlu;Cai, Ling;Zhang, Yu Shrike;Shah, Khalid
通讯作者：
Shah, Khalid

NK cells in the brain: implications for brain tumor development and therapy.

大脑中的 NK 细胞：对脑肿瘤发展和治疗的影响。