Blocking lung cancer progression with peptide delivering cell therapy platforms

利用肽递送细胞治疗平台阻止肺癌进展

• 批准号: 10546428
• 负责人: Richard Thomas O'Neil
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546428
• 关键词: Acids; Adoptive Transfer; Apoptosis; Aspirin; Cancer Etiology; Cancer Model; Cell Therapy; Cells; Cessation of life; Chronic; Clinical Trials; Combined Modality Therapy; Communication; Dendritic Cells; Disease; Effector Cell; Engineering; Engraftment; Excision; Immune; Immune response; Immunocompetent; Immunotherapy; Incidence; Label; Leucine Zippers; Ligands; Luciferases; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methods; Modality; Modeling; Modification; Monitor; Mus; Nature; Necrosis; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Patients; Peptides; Process; Proteins; Protocols documentation; RANTES; Recurrence; Solid Neoplasm; Source; T cell therapy; T-Lymphocyte; TNF gene; Technology; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Antigens; Tumor Tissue; United States; Woman; anti-cancer; antigen-specific T cells; base; cancer cell; cancer therapy; chemokine; chemotherapy; cytokine; cytotoxic; engineered T cells; improved; in situ vaccination; in vivo; malignant breast neoplasm; military veteran; mortality; mouse model; neoantigens; neoplastic cell; novel; novel therapeutics; receptor; recruit; response; subcutaneous; targeted delivery; therapeutic protein; tumor; tumor progression; tumor xenograft

For this project we propose to assess the utility of cell therapies for delivering the anti-cancer cytokines and chemokines in the context of non-small cell lung cancer models. Lung cancer is the leading cause of cancer related death in the Veteran population and metastasis is a major contributing factor to recurrence and mortality associated with non-small cell lung cancer. Aim 1 will take advantage TRAIL, a cytokine which induces apoptosis in cancer cells that is currently being evaluated as a therapeutic modality for treating lung cancer in ongoing clinical trials. For this project, antigen specific T cells transposon engineered to express high levels of soluble leucine zipper modified TRAIL will be adoptively transferred using a protocol that facilitates stable long term engraftment. The toxicity and off target effects of TRAIL cell therapy will first be assessed in healthy mice. We will then take advantage syngeneic orthotopic models of non- small cell lung cancer to evaluate the ability of TRAIL cell therapy to block metastasis. Combination cell therapy with acetylsalicylic acid will be assessed as a method of enhancing cancer cell sensitivity to TRAIL induced apoptosis and other candidate molecules that could be used in TRAIL combination therapy will be evaluated using a GFP based apoptosis screen. Aim 2 will evaluate the hypothesis that a cell therapy delivering the chemokine CCL5 in combination with TRAIL directly to tumors will augment immune-mediated tumor rejection. In Aim 3 we will determine if CCL5-TRAIL combination therapy blocks cancer progression and enhances survival in a murine orthotopic NSCLC model. This project represents a unique opportunity to examine the utility of delivering anticancer peptides with a cell therapy platform in the context of an immune competent mouse model of NSCLC. These studies will be useful in determining the efficacy of chronic systemic TRAIL therapy and tumor targeted CCL5/TRAIL combination therapy for blocking progression of lung cancer and augmenting tumor rejection.

对于这个项目，我们建议评估细胞疗法在提供抗癌药物方面的效用 非小细胞肺癌模型中的细胞因子和趋化因子。肺癌是 退伍军人群体中癌症相关死亡的主要原因，而转移是一个主要原因 与非小细胞肺癌相关的复发和死亡的影响因素。目标1 将利用 TRAIL，一种诱导癌细胞凋亡的细胞因子，目前 在正在进行的临床试验中被评估为治疗肺癌的一种治疗方式。为了 该项目将抗原特异性 T 细胞转座子设计为表达高水平的可溶性 亮氨酸拉链修饰的 TRAIL 将使用以下协议进行过继转移： 稳定的长期植入。 TRAIL细胞疗法的毒性和脱靶效应将首先被 在健康小鼠中进行评估。然后我们将利用非同源原位模型 小细胞肺癌评估 TRAIL 细胞疗法阻止转移的能力。 与乙酰水杨酸的联合细胞疗法将被评估为增强 癌细胞对 TRAIL 诱导的细胞凋亡和其他可能的候选分子的敏感性 将使用基于 GFP 的细胞凋亡筛选来评估 TRAIL 联合疗法中使用的药物。目的 2 将评估细胞疗法联合递送趋化因子 CCL5 的假设 将 TRAIL 直接作用于肿瘤将增强免疫介导的肿瘤排斥。在目标 3 中，我们将 确定 CCL5-TRAIL 联合疗法是否能阻止癌症进展并增强 小鼠原位 NSCLC 模型中的生存​​率。该项目代表了一个独特的机会 研究在以下情况下通过细胞治疗平台提供抗癌肽的效用 具有免疫能力的 NSCLC 小鼠模型。这些研究将有助于确定 慢性全身 TRAIL 治疗和肿瘤靶向 CCL5/TRAIL 组合的疗效 阻止肺癌进展和增强肿瘤排斥的疗法。