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A lung cancer vaccine based on exosomes of induced pluripotent stem cells

基于诱导多能干细胞外泌体的肺癌疫苗

基本信息

批准号：
10651014
负责人：
Chi Li
金额：
$ 40.24万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651014
关键词：
Adjuvant Adult Allogenic Antigen Presentation Autoimmune Responses Autoimmunity CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Vaccines Carcinoembryonic Antigen Categories Cells Chimera organism Clinical Trials Coculture Techniques Enterobacteria phage P1 Cre recombinase Exclusion Fibroblasts Frequencies Germ Cells Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Human Immune response Immunity Immunocompetent Immunotherapeutic agent Implant In Vitro Individual Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Modeling Monoclonal Antibodies Mus Operative Surgical Procedures Patients Pluripotent Stem Cells Prevention approach Probability Property Recurrence Residual Neoplasm Resistance Serum Somatic Cell Source Splenocyte Subgroup T cell response T-Cell Depletion TP53 gene Testing Tissues Tumor Antigens Tumor Immunity Tumor-Infiltrating Lymphocytes Tumorigenicity Vaccinated Vaccination Vaccines anti-cancer anticancer research antitumor effect cell type clinically relevant conventional therapy cytotoxic cytotoxic CD8 T cells early embryonic stage effectiveness evaluation effector T cell embryonic stem cell exosome experimental study immunogenic improved in vivo induced pluripotent stem cell innovation loss of function lung development lung tumorigenesis mouse model mutant neoplastic cell prevent response self-renewal success translational potential tumor tumor eradication tumor initiation tumorigenesis tumorigenic vaccination strategy

项目摘要

A lung cancer vaccine based on exosomes of induced pluripotent stem cells ABSTRACT A critical challenge in lung cancer research is to develop innovative vaccines to protect against pulmonary malignancy. Recent efforts to develop lung cancer vaccines have largely failed, probably due to their focus on inducing immune responses against individual lung tumor-associated antigens. If a lung cancer vaccine targets multiple antigens present only in lung tumors, but not in normal adult tissues, the chance of success will be greatly improved. Induced pluripotent stem cells (iPSCs) are reprogrammed from somatic cells and have the capacity of self-renewing and developing into all cell types of the adult body. It is known that iPSCs and tumor cells share carcinoembryonic antigens that are absent in normal adult tissues. Lung tumors also contain a subpopulation of tumor-initiating cells (TICs) with high tumorigenicity and self-renewal capability that contribute to the resistance to conventional therapies. Exploiting the antigenic similarity between tumor cells and iPSCs, we propose to thoroughly investigate efficacy of a lung cancer vaccine composed of exosomes from murine iPSCs expressing granulocyte-macrophage colony stimulating factor (GM-CSF) as an immunostimulatory adjuvant (iPSC-exo). We hypothesize that iPSC-exo vaccination prevents lung tumorigenesis by triggering CD8+ T cell-dependent immune responses and eradicating lung TICs. In this grant, we will investigate this hypothesis in two clinically relevant, immunocompetent murine lung tumor models. Two specific aims are proposed: 1) Investigate the translational potential of iPSC-exo vaccination against lung cancer; 2) Elucidate the mechanism by which iPSC-exo vaccination prevents lung cancer. We believe that the success of proposed experiments will lead to clinical trials of a similar vaccine against human pulmonary malignancy.

基于诱导多能干细胞外泌体的肺癌疫苗抽象的肺癌研究的一个关键挑战是开发创新疫苗来预防肺癌恶性肿瘤。最近开发肺癌疫苗的努力基本上失败了，可能是因为他们的重点是诱导针对个体肺部肿瘤相关抗原的免疫反应。如果肺癌疫苗的目标是多种抗原仅存在于肺部肿瘤中，但不存在于正常成人组织中，成功的机会将是大大改善。诱导多能干细胞 (iPSC) 由体细胞重新编程而成，具有自我更新和发育成成人身体所有细胞类型的能力。众所周知，iPSC 与肿瘤细胞共享正常成人组织中不存在的癌胚抗原。肺部肿瘤还含有具有高致瘤性和自我更新能力的肿瘤起始细胞（TIC）亚群，有助于对传统疗法的耐药性。利用肿瘤细胞和 iPSC 之间的抗原相似性，我们建议彻底研究由小鼠外泌体组成的肺癌疫苗的功效表达粒细胞巨噬细胞集落刺激因子 (GM-CSF) 作为免疫刺激剂的 iPSC 佐剂（iPSC-exo）。我们假设 iPSC-exo 疫苗接种通过触发来预防肺部肿瘤发生 CD8+ T 细胞依赖性免疫反应和根除肺部 TIC。在这笔赠款中，我们将对此进行调查在两个临床相关的免疫活性小鼠肺肿瘤模型中的假设。两个具体目标是提议：1) 研究 iPSC-exo 疫苗接种对抗肺癌的转化潜力； 2）阐明 iPSC-exo 疫苗接种预防肺癌的机制。我们相信提议的成功实验将导致针对人类肺部恶性肿瘤的类似疫苗进行临床试验。