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

• 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
• 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

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.

本页包含专有信息。请不要为评估和审查以外的任何目的分发。 项目总结/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）脑转移的时间约为4个月。虽然放射治疗仍然是第一个- 对于多发性脑转移瘤患者的一线治疗，在超过40%的患者中观察到复发。一 迫切需要一种新的治疗剂，以找到并根除这些残留的大脑 放疗后微转移。为了满足这一需求，我们建议使用神经干细胞（NSC）作为一种治疗方法。 靶向药物递送系统，用于治疗脑中剩余的肺癌微转移， 放疗神经干细胞已经证明了一种显着的，先天的能力，选择性地迁移到肿瘤。当 神经干细胞被编程为产生细胞毒性蛋白，已被证明迁移到并杀死胶质母细胞瘤肿瘤。 尽管NSC有望用于肿瘤靶向治疗，但NSC已被证明难以收获。同种异体 细胞激活免疫应答，促进NSC的清除，并降低其治疗窗。 需要自体神经干细胞来避免这种免疫应答，但由于位置和环境因素， 在大脑中发现的数量。为了解决这个问题，我们以前已经开发了一种方法， 使用慢病毒将人成纤维细胞快速转分化为诱导的神经干细胞（hiNSC） 含有诱导多能性转录因子Sox 2表达的基因。hiNSC是一种 个性化的肿瘤归巢治疗细胞系。然而，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调查hiNSC作为一种方法， 在脑内发现的非小细胞肺癌微转移。此外，我们将联合收割机 创新疗法与完善的放射治疗方案，以开发一个模型，反映当前 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，使用体内研究来确定 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，特别是关于发生的致敏或耐药， 在这种联合治疗之后。如果成功，这将是发展一个 一种新的、急需的治疗药物，用于治疗放疗后残留的NSCLC微转移， 从而降低肿瘤复发的风险和降低NSCLC的死亡率。