A Stem Cell Based Exosomal Vaccine for the Prevention of Cancer

用于预防癌症的基于干细胞的外泌体疫苗

基本信息

批准号：
10577271
负责人：
Chi Li
金额：
$ 21.95万
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：
2023-02-17 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577271
关键词：
Address Adenocarcinoma Adjuvant Adult Age Months Allogenic Antigens Autoimmunity Binding Biology CD34 gene CD8B1 gene Cancer Biology Cancer Etiology Cancer Patient Cancer Vaccines Carcinogens Cause of Death Cell Proliferation Cells Cessation of life Chemotherapy and/or radiation Consumption Data Daughter Development Disease Embryo Fibroblasts Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Growth Health Health Care Costs Human Immune Immune response Immunity Immunization Immunize Immunophenotyping Implant In Vitro Injections Invaded KRASG12D Laboratories Lewis Lung Carcinoma Life Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Messenger RNA Methodology MicroRNAs Modality Molecular Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Population Preventive vaccine Proliferating Property Proteins Proteomics Publishing Recurrence Recurrent disease Relapse Reporting Resistance Risk Rodent Solid Neoplasm Source Specificity Splenocyte Teratoma Testing Tissues Toxic effect Transgenic Organisms Tumor Antigens Tumor Immunity Tumor Stem Cells Tumor-infiltrating immune cells Vaccinated Vaccination Vaccines Validation Vesicle Work Xenograft procedure anti-cancer anti-tumor immune response antitumor effect cancer cell cancer initiation cancer prevention cancer therapy cancer type cell type conventional therapy cross reactivity cytotoxic efficacy testing embryonic antigen embryonic stem cell exosome experimental study human embryonic stem cell humanized mouse in vivo insight intercellular communication lung cancer prevention lung development lung tumorigenesis mouse model neoplastic cell novel oncofetal antigen patient derived xenograft model prevent prophylactic relapse risk response screening self-renewal stem cell biomarkers stem cell exosomes stem cells trait translational potential tumor tumor progression vaccination strategy vaccine development vaccine efficacy

项目摘要

PROJECT SUMMARY/ABSTRACT Lung cancer is a prevalent disease and consume many lives every year. Disease relapse, invasion and metastases are the main causes of death. Recent discoveries provide compelling evidence that at least some types of cancer are initiated and maintained by a small population of malignant cells called cancer-initiating stem cells (CICs). Relapse, invasion, and metastases are explained by the fact that CICs have a different biology than all the other tumor cells and, importantly, are resistant to chemotherapies and radiation. Lung CICs have been shown to represent about 1–15% of all tumor cells and can form tumors with injections as low as 100 cells. Evidence from published studies have demonstrated that human, as well as rodent, cancers contain populations of cells that express embryonic stem (ES) cell antigens. Cells containing these proteins also express markers used to identify lung CICs; therefore, we hypothesized that ES cells and CICs share several common molecular traits. To test this hypothesis, we vaccinated mice with exosomes derived from ES cells expressing GM-CSF and investigated whether an anti-tumor immune response was elicited. We discovered that ES cell-derived exosome-based vaccination strategy (ES-exo vaccine) is very effective in preventing both implantable and carcinogen-induced lung adenocarcinoma development without any detectable toxicity or signs of autoimmunity. Recently published results from our laboratory reveal that splenocytes from ES cell-immunized mice are preferentially cytotoxic to lung CICs. Experiments proposed in this application seek to expand these novel findings to convincingly demonstrate that ES-exo vaccine immunize against lung cancer-associated CICs and that anti-CIC immunity is responsible for preventing lung adenocarcinoma development. The anti-tumor activities of ES-exo vaccine as well as their immunostimulatory properties will be investigated in in vitro and in vivo lung cancer mouse models. Experiments proposed in this study will address the translational potential of our novel ES-exo vaccine as a cell-free prophylactic vaccine modality in implantable, transgenic and xenograft mouse models of lung cancer. One of the major goals of this application is to identify tumor antigens important for anti-lung cancer efficacy of ES-exo vaccine using a proteomics-based screening methodology. To fulfill the stated objectives, the following aims are proposed: 1) Investigate whether lung cancer-initiating cells are targets of ES cell-derived exosomes (ES-exo) vaccination- induced anti-tumor immunity, and 2) Evaluate the translational potential of ES cell-derived exosomes (ES-exo) as a novel cell-free vaccine for lung cancer. Our proposed study will provide important insights towards developing a safe prophylactic vaccine for lung cancer onset and/or recurrence.

项目概要/摘要肺癌是一种流行病，每年都会夺走许多人的生命。最近的发现提供了令人信服的证据，证明至少有一些死亡是由转移引起的。癌症类型是由一小群称为癌症起始的恶性细胞引发和维持的干细胞（CIC）可以通过 CIC 具有不同的特性来解释。其生物学特性优于所有其他肿瘤细胞，而且重要的是，肺对化疗和放射具有抵抗力。 CIC 已被证明约占所有肿瘤细胞的 1-15%，并且可以通过低剂量的注射形成肿瘤已发表的研究证据表明，人类以及啮齿动物都会患癌症。含有表达胚胎干 (ES) 细胞抗原的细胞群。也表达用于识别肺 CIC 的标记物；因此，我们发现 ES 细胞和 CIC 具有相同的特征为了验证这一假设，我们使用来自 ES 的外泌体对肺炎小鼠进行了研究。表达 GM-CSF 的细胞并研究是否引发抗肿瘤免疫反应。发现基于 ES 细胞衍生的外泌体的疫苗接种策略（ES-exo 疫苗）非常有效预防植入性肺腺癌和致癌物诱发的肺腺癌发展，无需任何我们实验室最近发表的结果表明，可检测到的毒性或自身免疫的迹象。来自 ES 细胞免疫小鼠的脾细胞优先对肺 CIC 产生细胞毒性。本申请旨在扩展这些新发现，以令人信服地证明 ES-exo 疫苗针对肺癌相关的 CIC 进行免疫，抗 CIC 免疫负责预防肺癌 ES-exo 疫苗的抗肿瘤活性及其免疫刺激作用。在此提出的实验将在体外和体内研究肺癌小鼠模型的特性。研究将探讨我们的新型 ES-exo 疫苗作为无细胞预防性疫苗的转化潜力该研究的主要目标之一是在肺癌的植入式、转基因和异种移植小鼠模型中进行治疗。应用是使用ES-exo疫苗来鉴定对于抗肺癌功效重要的肿瘤抗原为了实现既定目标，提出以下目标：1) 研究肺癌起始细胞是否是 ES 细胞衍生的外泌体 (ES-exo) 疫苗接种的目标 - 诱导抗肿瘤免疫，2) 评估 ES 细胞来源的外泌体 (ES-exo) 的翻译潜力作为一种新型的肺癌无细胞疫苗，我们提出的研究将为研究提供重要的见解。开发针对肺癌发作和/或复发的安全预防性疫苗。