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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.

一种基于诱导多能干细胞外体的肺癌疫苗摘要肺癌研究中的一个关键挑战是开发预防肺癌的创新疫苗。恶毒。最近开发肺癌疫苗的努力在很大程度上失败了，可能是因为他们专注于诱导针对单个肺肿瘤相关抗原的免疫反应。如果肺癌疫苗针对的是多种抗原只存在于肺肿瘤中，而不存在于正常成人组织中，成功的机会将是有很大的进步。诱导多能干细胞(IPSCs)是由体细胞重新编程而来，具有自我更新和发育成成人身体的所有细胞类型的能力。已知IPSCs与肿瘤细胞共享正常成人组织中不存在的癌胚抗原。肺肿瘤还含有一种具有高致瘤性和自我更新能力的肿瘤启动细胞(TIC)亚群对传统疗法的抵抗力。利用肿瘤细胞和IPSCs之间的抗原性相似性，我们建议彻底研究一种由小鼠外切体组成的肺癌疫苗的疗效。表达粒细胞巨噬细胞集落刺激因子的IPSCs作为免疫刺激因子佐剂(IPSC-exo)。我们假设IPSC-exo疫苗通过触发 CD8+T细胞依赖的免疫反应和消除肺部抽搐。在这笔拨款中，我们将调查这一点两种临床相关、免疫活性的小鼠肺癌模型的假说。两个具体目标是建议：1)研究IPSC-exo疫苗对肺癌的翻译潜力；2)阐明 IPSC-exo疫苗预防肺癌的机制。我们相信，建议的成功实验将导致针对人类肺部恶性肿瘤的类似疫苗的临床试验。