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: 10266015
• 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/10266015
• 关键词: Blocking; lung; cancer; progression; peptide

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.

在这个项目中，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 在退伍军人人群中，癌症相关死亡和转移的主要原因是 与非小细胞肺癌相关的复发和死亡的促成因素。目标1 将利用TRAIL，一种诱导癌细胞凋亡的细胞因子，目前 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 这个项目，抗原特异的T细胞转座子被设计成表达高水平的可溶性 亮氨酸拉链修改的TRAIL将使用促进 长期稳定的植入物。TRAIL细胞疗法的毒性和非靶向效应将首先是 在健康的小鼠身上进行评估。然后我们将利用非同种异体原位模型 评价TRAIL细胞治疗对小细胞肺癌的阻断转移能力。 联合细胞疗法和乙酰水杨酸将被评估为一种增强 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 用于TRAIL联合治疗的药物将使用基于GFP的细胞凋亡筛查进行评估。目标 2将评估一种联合输送趋化因子CCL5的细胞疗法的假设 TRAIL直接作用于肿瘤将增强免疫介导的肿瘤排斥反应。在《目标3》中，我们将 确定CCL5-TRAIL联合治疗是否阻止癌症进展并增强 小鼠原位非小细胞肺癌模型的存活率。这个项目代表着一个独特的机会 研究使用细胞治疗平台输送抗癌肽的效用 一种免疫功能良好的非小细胞肺癌小鼠模型。这些研究将有助于确定 慢性全身TRAIL治疗与肿瘤靶向CCL5/TRAIL联合治疗的疗效 阻断肺癌进展和增强肿瘤排斥反应的治疗。