权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10355476
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/10355476
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 Image Immune Immune Evasion Immune response Immunohistochemistry Immunomodulators Immunotherapy Infiltration Injection of therapeutic agent Interferon-beta Interferons Laboratories Ligands 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 Savings Simplexvirus Surgically-Created Resection Cavity Testing Therapeutic Thymidine Kinase Time Translating Treatment Efficacy Tumor Debulking Tumor Suppressor Proteins Tumor-infiltrating immune cells Up-Regulation adult stem cell base bioluminescence imaging cancer type clinical care clinical translation clinically translatable cytotoxic design engineered stem cells fluorescence imaging imaging biomarker immune checkpoint blockade immune resistance immunomodulatory therapies immunoregulation in vivo mouse model mutant neoplastic cell neuropathology post-transplant prevent programmed cell death ligand 1 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, IFN has been known to upregulate program cell death ligand 1 (PD-L1) expression on tumor cells, thus hindering the immunomodulatory function of IFN. 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.

总结