Engineering stem cell therapies to understand and overcome glioblastoma adaption

工程干细胞疗法以了解和克服胶质母细胞瘤适应

• 批准号: 9447282
• 负责人: Shawn Hingtgen
• 金额: $ 33.22万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-26 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9447282
• 关键词: Address; Adult; Affect; Aftercare; Alpha Cell; Animals; Apoptotic; Autologous; Behavior; Blood - brain barrier anatomy; Brain; Cell Therapy; Cells; Chemotherapy-Oncologic Procedure; Clinic; Clinical; Diffuse; Disease; Distant; Dose; Drug Carriers; Drug Delivery Systems; Engineering; Event; Excision; Failure; Fibroblasts; Future; Genetic Engineering; Genetically Engineered Mouse; Glioblastoma; Goals; Grant; Home environment; Homing; Human; Immune; Immune system; In Vitro; Infusion procedures; Injection of therapeutic agent; Luciferases; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Molecular; Mus; Oncogenes; Operative Surgical Procedures; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Process; Proliferating; Recurrence; Resected; Resistance; Seeds; Site; Solid; Somatic Cell; Surgically-Created Resection Cavity; TNFSF10 gene; Technology; Testing; Therapeutic; Tissues; Transplantation; Tumor Stem Cells; Ventricular; Work; Xenograft Model; Xenograft procedure; base; bioluminescence imaging; cancer cell; cancer invasiveness; cell killing; cell type; clinically relevant; cytotoxic; defined contribution; gene product; improved; killings; migration; mouse model; neoplastic cell; nerve stem cell; novel; preclinical study; prevent; response; stem cell therapy; transcription factor; transdifferentiation; tumor

Project Summary/Abstract Genetically engineered neural stem cells (NSCs) are a promising therapy for the highly aggressive brain cancer Glioblastoma (GBM). Engineered NSCs have unique tumor-homing capacity that allows them to deliver anti-cancer gene products directly into local and invasive GBM foci. Preclinical studies by our group and others have shown tumoricidal NSCs routinely reduce orthotopic GBM xenografts between 70-90% and significantly extend survival of tumor-bearing mice. Yet, these dramatic initial reductions in GBM volumes are not maintained and treatment durability remains a major challenge for NSC-based therapy. GBM escape occurs after treatment with NSCs carrying different therapeutic payloads and in pre-clinical models of both solid and post-surgical GBM. We recently discovered that novel tumor-homing drug delivery vehicles with robust anti- cancer activity can be developed from “induced neural stem cells” (iNSCs) using cellular reprogramming technology, referred to as transdifferentiation (TD). Tumoricidal iNSC therapy reduced GBM xenografts 230- fold in 4 weeks and more than doubled survival. Similar to wild-type NSC therapy, the tumors were not eradicated and the GBMs re-developed. The events mediating the regrowth of GBMs in response to single- agent NSC/iNSC therapy are unknown. Our results show that transplanted iNSCs drug carriers are cleared from the brain, but repeated intracerebroventricular (ICV) infusion restores carrier levels. We also have evidence that GBM cells become resistant to iNSC-delivered drugs. This allows us to hypothesize that GBM resistance to iNSC therapy can be overcome by repeat administration to address carrier loss and multi-agent iNSC delivery to address tumor resistance. With this grant we propose to test this hypothesis, defining the events that contribute to the dynamic adaption of GBM during NSC treatment and develop strategies to convert the initial tumor kill into sustained GBM suppression. We will investigate carrier clearance, homing, and tumor resistance throughout GBM adaption and recurrence. We will then modulate iNSC therapy through repeated dosing via ICV infusion and delivery of iNSCs carrying multi-drug payloads with the goal of improving treatment durability by overcoming iNSC loss and the emergence of GBM foci that are resistant to single-agent treatments. All testing will be done using our novel surgical resection models of murine-derived GBM cells in immune-competent animals and patient-derived CD133+ human GBM cells to maximize the clinical relevancy of our finding and understand the impact of the immune system on iNSC treatment durability. The results of these studies are essential for creating durable NSC-based tumor therapies capable of producing long-lasting GBM suppression in patient trials.

项目总结/摘要 基因工程神经干细胞（NSCs）是一种很有前途的治疗高度侵袭性大脑的方法 恶性胶质母细胞瘤（GBM）。工程化的NSC具有独特的肿瘤归巢能力， 抗癌基因产物直接进入局部和侵袭性GBM病灶。我们小组和其他人的临床前研究 已经显示杀肿瘤的NSC常规地减少原位GBM异种移植物70-90%，并且显著地 延长荷瘤小鼠的存活时间。然而，GBM量的这些戏剧性的初始减少并不是 维持和治疗持久性仍然是基于NSC的治疗的主要挑战。发生GBM逃逸 在用携带不同治疗有效载荷的NSC治疗后， 术后GBM我们最近发现，具有强大抗肿瘤活性的新型肿瘤归巢药物递送载体， 利用细胞重编程， 技术，称为转分化（TD）。杀肿瘤iNSC疗法减少GBM异种移植物230- 4周内增加一倍，存活率增加一倍以上。与野生型NSC治疗相似， 被根除，GBM被重新开发。介导GBM再生长的事件响应于单- NSC/iNSC治疗剂未知。我们的研究结果表明，移植的iNSC药物载体被清除， 但是反复的脑室内（ICV）输注可以恢复载体水平。我们也有 GBM细胞对iNSC递送的药物产生耐药性的证据。这使我们能够假设GBM 对iNSC疗法的抗性可以通过重复施用来克服，以解决载体丢失和多药剂 iNSC递送以解决肿瘤抗性。有了这笔赠款，我们打算测试这一假设，定义 在NSC治疗期间有助于GBM动态适应的事件，并制定转换策略 将最初的肿瘤杀伤转化为持续的GBM抑制。我们将研究载体清除，归巢，和肿瘤 在整个GBM适应和复发期间的抗性。然后，我们将通过重复的免疫调节来调节iNSC治疗。 通过ICV输注和递送携带多种药物有效载荷的iNSC进行给药，目的是改善治疗 通过克服iNSC损失和出现对单药耐药的GBM病灶， 治疗。所有的测试将使用我们的新的鼠源性GBM细胞的手术切除模型进行， 免疫活性动物和患者来源的CD 133+人GBM细胞，以最大限度地提高临床相关性 我们的发现和了解免疫系统对iNSC治疗持久性的影响。的结果 这些研究对于创造持久的基于神经干细胞的肿瘤疗法至关重要， 患者试验中的GBM抑制。