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.

在这个项目中，我们建议评估细胞疗法用于递送抗癌药物的效用。 细胞因子和趋化因子在非小细胞肺癌模型中的作用。肺癌是 退伍军人癌症相关死亡的主要原因是转移， 非小细胞肺癌的复发率和死亡率。要求1 将利用肿瘤坏死因子相关凋亡配体（TRAIL），这是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治疗方式。为 该项目，抗原特异性T细胞转座子工程表达高水平的可溶性 亮氨酸拉链修饰的TRAIL将使用有助于 稳定的长期植入。TRAIL细胞疗法的毒性和脱靶效应将首先被研究。 在健康小鼠中进行评估。然后，我们将利用非- 小细胞肺癌，以评估TRAIL细胞疗法阻断转移的能力。 将评估与乙酰水杨酸的组合细胞疗法作为增强免疫应答的方法。 癌细胞对TRAIL的敏感性诱导凋亡和其他候选分子， 将使用基于GFP的细胞凋亡筛选来评估用于TRAIL组合疗法的细胞凋亡。目的 2将评估这样的假设，即递送趋化因子CCL 5的细胞疗法与递送趋化因子CCL 5的细胞疗法组合， 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， 确定CCL 5-TRAIL联合治疗是否能阻断癌症进展并增强 小鼠原位NSCLC模型中的存活率。这个项目是一个独特的机会， 检查在以下情况下用细胞治疗平台递送抗癌肽的效用： NSCLC的免疫活性小鼠模型。这些研究将有助于确定 慢性全身性TRAIL治疗和肿瘤靶向CCL 5/TRAIL联合治疗的疗效 用于阻断肺癌进展和增强肿瘤排斥的治疗。