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

本页面包含专有信息。除评估和审查外，请不要出于任何目的分发。 项目摘要/摘要 肺癌是最常见的扩散到大脑的原发癌症。慢性阻塞性肺疾病患者的中位生存期 非小细胞肺癌(NSCLC)脑转移约为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LINE治疗，超过40%的患者观察到复发。一个 迫切需要新的治疗剂来寻找和根除这些残留的大脑 放射治疗后的微转移。为了满足这种需求，我们建议使用神经干细胞(NSCs)作为 靶向给药系统清除肺癌术后脑内残留微转移 放射治疗。神经干细胞已经显示出一种非凡的、与生俱来的选择性迁移到肿瘤的能力。什么时候 神经干细胞被编程产生细胞毒蛋白，已被证明可以迁移到胶质母细胞瘤并杀死肿瘤。 尽管NSCs有望用于肿瘤靶向治疗，但事实证明NSCs很难获得。同种异体 细胞激活免疫反应，促进神经干细胞的清除，缩短治疗窗口。 需要自体神经干细胞来避免这种免疫反应，但由于位置和位置的原因，收集不切实际 在大脑中发现的数量。为了解决这个问题，我们以前开发了一种方法 利用慢病毒快速将人成纤维细胞转化为诱导神经干细胞 含有诱导多能性转录因子Sox2表达的基因。HiNSC是一种 个性化的肿瘤归巢治疗细胞系。然而，之前关于hiNSCs的研究已经 专注于原发性脑癌的治疗。这项工作将是第一次将hiNSCs作为一种方法进行研究 根除在大脑中发现的影响深远的非小细胞肺癌微转移。此外，我们将结合这一点 利用成熟的放射治疗方案进行创新治疗，以开发反映当前情况的模式 治疗方案。为了评估治疗性hNSCs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，利用体内研究确定 HNSC在放疗后的迁移、持久性和有效性，以及单细胞mRNA测序 阐明肿瘤和肿瘤床的异质性，特别是关于敏化或耐药性的异质性 在这次联合治疗之后。如果成功，这将是开发一个 新的急需的治疗剂来清除放射治疗后残留的非小细胞肺癌微转移， 从而降低肿瘤复发的风险，降低非小细胞肺癌的死亡率。

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.