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: 9926708
• 负责人: Richard Thomas O'Neil
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 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/9926708
• 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; In Situ; 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; Population; 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; Vaccination; Veterans; Woman; anti-cancer; antigen-specific T cells; base; cancer cell; cancer therapy; chemokine; chemotherapy; cytokine; cytotoxic; engineered T cells; improved; in vivo; malignant breast neoplasm; 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在传递抗癌药物方面的效用