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新型靶向溶瘤病毒细胞疗法 被普通感冒无害病毒（呼吸道合胞体）感染的间充质干细胞（MSC） 用于治疗肺癌的病毒（RSV），肺癌是癌症中的头号杀手 尽管治疗方法取得了进步并改善了结果，但 5 年生存率仍然较低。 非小细胞肺癌 (NSCLC) 的发病率仍然非常低（15% 或更低），这构成了 约 85% 的肺癌患者的生存率如此之低。 异质性和对经典化疗和放疗耐药性的发展，下划线 需要开发新的非姑息治疗策略。 病毒疗法已成为传统化疗和放射疗法的潜在替代方案， 此外，它们在肺癌中的应用仍然有限。 总体而言，这仍然是一个关键障碍，特别是对于肺癌来说，仍然是一个未满足的主要需求。 针对肺癌的靶向溶瘤病毒细胞疗法概念的动机来自 首先是 MSC，一种通常已知具有内在肿瘤的细胞类型。 热带特性，被发现对 RSV 高度敏感，感染率 >90%，表明 使用 RSV 感染的 MSC 进行肿瘤靶向和肿瘤杀伤的潜力是巨大的。 RSV 感染的 MSC 上调吲哚胺-2, 3-双加氧酶 (IDO) 的挑战 抑制肿瘤免疫，从而有助于肿瘤发生。然而，人们发现IDO-。 缺陷的 hMSC 仍然对 RSV 高度敏感，同时减弱肿瘤抑制作用。 其次，非结构蛋白 1 (NS1) 缺陷 (ΔNS1) RSV 在肺中以高病毒滴度复制 与正常 WI-38 二倍体肺细胞相比，这些发现共同导致了肿瘤细胞的出现。 假设 ΔNS1 RSV 感染的 IDO 缺陷 MSC 将保留肿瘤趋向性，并且 将有助于开发针对肺癌的靶向溶瘤病毒细胞疗法。 假设将在以下三个具体目标中得到检验！ 在目标#1中，计划使用以下方法开发和表征稳定的 IDO 缺陷 hMSC 细胞系 CRISPR方法并检查野生型和工程化（ΔNS1）的抗肿瘤活性潜力 体外和活检来源的 3D 多细胞肿瘤样培养物中 RSV 感染的 MSC (RMSC) 在目标 2 中，建议评估 RMSC 的体内抗癌潜力。 肺癌免疫活性同基因原位模型并评估其潜力 调节抗肿瘤免疫 在目标#3 中，RMSC 在调节细胞凋亡中的作用。 将研究病毒抗原。 总体而言，靶向 RMSC 疗法有望提供高度创新和有效的治疗方法。 PI 具有独特的优势来实施拟议的治疗方法。 研究开发一种新的肺癌治疗方法，该方法可能适用于其他癌症 肿瘤疾病所需的所有方法、试剂和合作均已到位。 成功完成这一拟议项目，在肺癌领域具有最高的临床影响。