Tumor targeted engineered stem cells for treatment of lung cancer

肿瘤靶向工程干细胞用于治疗肺癌

• 批准号: 10045941
• 负责人: SUBHRA MOHAPATRA
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10045941
• 关键词: 3-Dimensional; Antineoplastic Agents; Apoptosis; Biopsy; CRISPR/Cas technology; Cancer Patient; Cell Death; Cell Line; Cell Therapy; Cells; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Common Cold Virus; Data; Development; Dioxygenases; Diploidy; Disease; Engineering; Epithelial Cells; Human; Immunocompetent; In Vitro; Infection; Interferon-beta; Lewis Lung Carcinoma; Lung; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mesenchymal Stem Cells; Methods; Mitochondria; Modeling; Motivation; Non-Small-Cell Lung Carcinoma; Nonstructural Protein; Oncolytic; Oncolytic viruses; Outcome; Positioning Attribute; Property; Proteins; Reagent; Resistance development; Respiration; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Survival Rate; System; Testing; Therapeutic; Translating; Tropism; Tumor Immunity; Up-Regulation; Viral; Viral Antigens; Viral Proteins; Voltage-Dependent Anion Channel; WI 38 cell; anti-cancer; base; bronchial epithelium; cancer cell; cancer diagnosis; cancer heterogeneity; cancer therapy; cell type; chemoradiation; clinically relevant; cytochrome c; engineered stem cells; in vivo; indoleamine; infection rate; innovation; lung cancer cell; military veteran; mouse model; neoplastic; neoplastic cell; novel; novel strategies; novel therapeutic intervention; oncolytic virotherapy; programs; stem cell therapy; tumor; tumorigenesis; virus related cancer

This proposal aims to explore and test a novel targeted oncolytic viro-cell therapy using the mesenchymal stem cells (MSCs) infected by harmless common cold virus, the respiratory syncytial virus (RSV) for treatment of lung cancers, which is the number one killer among cancers worldwide. Despite advances in the treatment and improvement in outcomes, the 5-year survival rates remain very poor (15% or less) for non–small cell lung cancers (NSCLC), which constitute ~85% of all lung cancer patients. Such poor survival rates combined with lung cancer heterogeneity and development of resistance to classical chemo- and radio-therapies, underscore the need for development of novel non-palliative therapeutic strategies. Though oncolytic virotherapies have emerged as a potential alternative to traditional chemo- and radio-therapies, their application to lung cancers remain limited. Also, inability to target oncolytic viruses to tumors in general remains a critical barrier and particularly for lung cancers remains a major unmet need. The motivation for the concept of targeted oncolytic viro-cell therapy against lung cancer comes from two major developments. First, MSCs, a cell-type generally known to have intrinsic tumor tropic properties, were found to be highly susceptible to RSV, with >90% infection rate, suggesting the use of RSV-infected MSCs for both tumor targeting and tumor killing. This potential was challenged by upregulation of indoleamine-2, 3-dioxygenase (IDO) by RSV-infected MSCs, which suppresses tumor immunity and thus aid in tumorigenesis. However, it was found that IDO- deficient hMSCs remain highly susceptible to RSV while alleviating the tumor suppressive effect. Second, nonstructural protein 1 (NS1) deficient (ΔNS1) RSV replicates with high viral titer in lung tumor cells, compared to the normal WI-38 diploid lung cells. Together these findings have led to the hypothesis that the ∆NS1 RSV-infected IDO-deficient MSCs will retain tumor tropism and would lend themselves to develop a targeted oncolytic viro-cell therapy against lung cancers. This hypothesis will be tested in the following three specific aims. ! In aim #1, it is planned to develop and characterize a stable IDO-deficient hMSC cell line using the CRISPR method and examine the anti-tumor activity potential of wild type and engineered (ΔNS1) RSV-infected MSCs (RMSCs) in 3D multicell tumoroid cultures in vitro and biopsy-derived tumoroids ex vivo. In aim #2, it is proposed to assess the anti-cancer potential of RMSCs in vivo in immunocompetent syngeneic orthotopic model of lung cancer and evaluate their potential to modulate anti-tumor immunity. In aim #3 the effects of RMSC in modulating apoptosis induced by viral antigens will be investigated. Overall, the targeted RMSC therapy is expected to provide a highly innovative and effective approach for treatment of lung cancers. The PIs are uniquely positioned to conduct the proposed studies to develop a novel therapeutic approach for lung cancers, which may apply to other neoplastic diseases. All the required methods, reagents and collaborations are in place for the successful completion of this proposed program with highest clinical impact in the lung cancer field.

该提案旨在探索和测试一种针对性的针对性的溶瘤性毒细胞疗法 被无害的普通冷病毒感染的间充质干细胞（MSC），呼吸道突触 用于治疗肺癌的病毒（RSV），这是癌症中的第一杀手 全世界。尽管治疗和结果的改善取得了进步，但生存期为5年 对于构成的非小细胞肺癌（NSCLC）的率仍然很差（15％或更低） 所有肺癌患者中有85％。如此差的生存率结合了肺癌 对经典化学和放射性的耐药性的异质性和发展，下划线 需要开发新的非帕利亚治疗策略。虽然溶瘤 病毒疗法已成为传统化学和放射性治疗的潜在替代品， 他们在肺癌中的应用仍然有限。而且，无法将溶瘤病毒靶向肿瘤 通常，仍然是关键的障碍，尤其是对于肺癌仍然是一个主要的未满足需求。 针对肺癌的有针对性的溶瘤性维罗细胞疗法概念的动机是 来自两个主要发展。首先，MSC，一种通常已知具有内在肿瘤的细胞类型 发现热带特性高度容易受到RSV的影响，感染率> 90％，表明 使用RSV感染的MSC用于肿瘤靶向和肿瘤杀死。这种潜力是 由RSV感染的MSC的上调吲哚胺-2，3-二氧酶（IDO）的挑战， 抑制肿瘤免疫，从而有助于肿瘤发生。但是，发现ido- 缺乏HMSC仍然非常容易受到RSV的影响，同时减轻了肿瘤抑制作用。 其次，非结构蛋白1（NS1）缺乏（ΔNS1）RSV在肺中以高病毒滴度重复 与正常的WI-38二倍体肺细胞相比，肿瘤细胞。这些发现一起导致了 ∆NS1 RSV感染的IDO缺陷MSC将保留肿瘤的肿瘤向上和 会借给自己针对肺癌的有针对性的溶瘤毒细胞疗法。这 假设将在以下三个特定目标中进行检验。 在AIM＃1中，计划使用稳定的IDO缺陷HMSC单元线来开发和表征 CRISPR方法并检查野生型和工程的抗肿瘤活性潜力（ΔNS1） 在体外和活检衍生的3D多细胞瘤培养物中的RSV感染的MSC（RMSC） 肿瘤生体。在AIM＃2中，建议评估RMSC在体内的抗癌潜力 肺癌的免疫能力合成原位模型，并评估其潜力 调节抗肿瘤免疫。在AIM＃3中，RMSC在调节由 病毒抗原将进行研究。 总体而言，有针对性的RMSC疗法有望提供高度创新和有效的 治疗肺癌的方法。 PI是唯一的定位以进行提出的 为开发一种新型肺癌热方法的研究，该方法可能适用于其他 肿瘤疾病。所有必需的方法，试剂和协作都适用于 成功完成该提议的计划，在肺癌领域具有最大的临床影响。