Therapeutic Engineered Stem Cells as a New Adjuvant Therapy for Non-Small Cell Lung Cancer Brain Metastases

治疗性工程干细胞作为非小细胞肺癌脑转移的新辅助疗法

基本信息

批准号：
10202509
负责人：
Alison R. Mercer-Smith
金额：
$ 5.1万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2019-07-11 至 2023-07-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202509
关键词：
Address Adjuvant Adjuvant Therapy Aftercare Allogenic Apoptosis Area Autologous Autopsy Basic Science Beds Biological Assay Brain Brain Neoplasms Cell Line Cells Cessation of life Chemotherapy and/or radiation Clinic Clinical Coculture Techniques Combined Modality Therapy Cranial Irradiation Cytotoxic agent Development Diagnosis Disease Distant Distant Metastasis Drug Delivery Systems Drug Targeting Effectiveness Engineering Ensure Evaluation Fibroblasts Foundations Genes Genetic Engineering Glioblastoma Harvest Heterogeneity Home Homing Human Human Engineering Hypoxia Immune response Immune system Implant In Vitro Injections Innovative Therapy Lentivirus Lesion Ligands Location Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Mentors Metastatic malignant neoplasm to brain Methods Micrometastasis Modeling Mus Necrosis Non-Small-Cell Lung Carcinoma Nonmetastatic Optical reporter Pathway interactions Patients Process Production Property Proteins Radiation Radiation therapy Radiosurgery Recurrence Regimen Research Residual state Resistance Risk Signal Transduction Solid TNF gene Testing Therapeutic Therapeutic Agents Therapeutic Effect Training Translating Treatment Protocols Tumor Stem Cells Tumor Volume Work bioluminescence imaging cancer cell chemokine combat combinatorial cytokine cytotoxic engineered stem cells improved in vivo lung cancer cell migration mortality mouse model neoplastic cell nerve stem cell novel therapeutics optimal treatments prevent rapid technique response single cell mRNA sequencing single-cell RNA sequencing standard of care stem cell therapy targeted treatment therapy resistant transcription factor treatment optimization tumor tumor heterogeneity

项目摘要

This page contains proprietary information. Please do not distribute for any purposes other than evaluation and review. PROJECT SUMMARY/ABSTRACT Lung cancer is the most common primary cancer to spread to the brain. The median survival for patients with non-small cell lung cancer (NSCLC) brain metastases is about 4 months. While radiotherapy remains a first- line treatment for patients with multiple brain metastases, recurrence is observed in over 40% of patients. A new therapeutic agent is desperately needed in order to find and eradicate these remaining brain micrometastases post-radiotherapy. To address this need, we propose using neural stem cells (NSCs) as a targeted drug delivery system to scavenge for remaining lung cancer micrometastases in the brain after radiotherapy. NSCs have demonstrated a remarkable, innate ability to selectively migrate to tumors. When programmed to produce cytotoxic proteins, NSCs have been proven to migrate to and kill glioblastoma tumors. Despite the promise of NSCs for tumor-targeted treatment, NSCs have proven difficult to harvest. Allogeneic cells activate the immune response, promote clearance of NSCs, and decrease their therapeutic window. Autologous NSCs are needed to avoid this immune response but are impractical to collect due to location and quantities found in the brain. In order to combat this problem, we have previously developed a method of rapidly transdifferentiating human fibroblasts into induced neural stem cells (hiNSCs) using a lentivirus containing the gene to induce expression of the multipotency transcription factor, Sox2. The hiNSCs are a personalized, tumor-homing therapeutic cell line. However, previous research surrounding hiNSCs has focused on the treatment of primary brain cancer. This work will be the first to investigate hiNSCs as a method of eradicating far-reaching NSCLC micrometastases found in the brain. Moreover, we will combine this innovative therapy with well-established radiotherapy regimens in order to develop a model that reflects current treatment regimens. In order to assess the potential of therapeutic hiNSCs as an adjuvant treatment for NSCLC brain micrometastases, we will perform treatment optimization in vitro, use in vivo studies to determine the migration, persistence, and efficacy of hiNSC following radiotherapy, and single-cell mRNA sequencing to elucidate tumor and tumor bed heterogeneity, particularly regarding sensitization or resistance, that occurs after this combination therapy. If successful, this will be important foundational work in the development of a new, much-needed therapeutic agent to scavenge for NSCLC micrometastases remaining after radiotherapy, thus reducing the risk of tumor recurrence and decreasing the mortality of NSCLC.

此页面包含专有信息。请勿出于评价、评论以外的任何目的传播。项目概要/摘要肺癌是最常见的扩散到大脑的原发性癌症。患者的中位生存期非小细胞肺癌（NSCLC）脑转移时间约为4个月。虽然放射治疗仍然是首选治疗多发性脑转移瘤患者接受一线治疗后，超过 40% 的患者出现复发。一个迫切需要新的治疗剂来找到并根除这些残留的大脑放射治疗后的微转移。为了满足这一需求，我们建议使用神经干细胞（NSC）作为靶向药物输送系统清除术后大脑中剩余的肺癌微转移放射治疗。神经干细胞已表现出卓越的、选择性迁移至肿瘤的先天能力。什么时候 NSCs 被编程为产生细胞毒性蛋白，已被证明可以迁移至胶质母细胞瘤肿瘤并杀死它们。尽管 NSC 有望用于肿瘤靶向治疗，但事实证明 NSC 很难收获。同种异体细胞激活免疫反应，促进 NSC 的清除，并减少其治疗窗口。需要自体 NSC 来避免这种免疫反应，但由于位置和条件的原因，收集起来不切实际。大脑中发现的数量。为了解决这个问题，我们之前开发了一种方法使用慢病毒将人成纤维细胞快速转分化为诱导神经干细胞 (hiNSC) 含有诱导多能转录因子 Sox2 表达的基因。 hiNSC 是个性化的肿瘤归巢治疗细胞系。然而，之前围绕 hiNSC 的研究专注于原发性脑癌的治疗。这项工作将是第一个研究 hiNSC 作为方法的工作根除大脑中发现的影响深远的非小细胞肺癌微转移。此外，我们将结合此创新疗法与完善的放射治疗方案，以开发反映当前情况的模型治疗方案。为了评估治疗性 hiNSC 作为辅助治疗的潜力 NSCLC脑微转移，我们将在体外进行治疗优化，利用体内研究来确定放射治疗后 hiNSC 的迁移、持久性和功效，以及单细胞 mRNA 测序阐明发生的肿瘤和瘤床异质性，特别是关于致敏或耐药性经过这种联合治疗。如果成功的话，这将是开发一个重要的基础工作。急需的新治疗剂，用于清除放疗后残留的 NSCLC 微转移，从而降低肿瘤复发的风险并降低NSCLC的死亡率。