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：
9982039
负责人：
Alison R. Mercer-Smith
金额：
$ 3.7万
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/9982039
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 environment Homing Human Human Engineering Hypoxia Immune response Immune system Implant In Vitro Injections Innovative Therapy 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 Subfamily lentivirinae 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 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。除评估和审查外，请不要出于任何目的分发。项目摘要/摘要肺癌是传播到大脑的最常见的原发性癌症。患者的中位生存期非小细胞肺癌（NSCLC）脑转移约为4个月。放疗仍然是首先超过40％的患者观察到多种脑转移患者的线治疗，复发。一个迫切需要新的治疗剂才能找到和消除这些剩余的大脑微量转移疗法后。为了满足这一需求，我们建议将神经干细胞（NSC）用作有针对性的药物输送系统清除大脑中剩余的肺癌微转移放疗。 NSC表现出具有选择性迁移到肿瘤的显着，天生的能力。什么时候已被编程以产生细胞毒性蛋白，NSC已被证明可以迁移并杀死胶质母细胞瘤肿瘤。尽管NSC有望接受以肿瘤为目标的治疗，但NSC已被证明很难收获。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，但由于位置和大脑中发现的数量。为了解决这个问题，我们以前已经开发了一种使用慢病毒病毒将人的成纤维细胞迅速转变为诱导的神经干细胞（HINSC）包含基因诱导多能转录因子SOX2的表达。 HINSC是一个个性化的，肿瘤的治疗细胞系。但是，以前围绕HINSC的研究专注于治疗原发性脑癌。这项工作将是第一个作为一种方法调查HINSC的工作消除大脑中发现的深远NSCLC微型转移。而且，我们将结合起来具有完善的放射治疗方案的创新疗法，以开发一个反映当前的模型治疗方案。为了评估治疗性HINSC作为辅助治疗的潜力 NSCLC脑微转移酶，我们将在体外进行治疗优化，在体内研究中确定放疗后HINSC的迁移，持久性和功效，以及单细胞mRNA测序阐明肿瘤和肿瘤床异质性，尤其是在敏化或抵抗方面在这种组合疗法之后。如果成功，这将是发展的重要基础工作新的，急需的治疗剂，清除放射疗法后剩余的NSCLC微型转移，从而降低了肿瘤复发的风险并降低了NSCLC的死亡率。