Development of tumor based antigen presenting cells

基于肿瘤的抗原呈递细胞的开发

• 批准号: 6904892
• 负责人: RICHARD G CARROLL
• 金额: $ 27.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6904892
• 关键词: NOD mouse; SCID mouse; T lymphocyte; antigen presenting cell; biotechnology; cell line; clinical research; female; human subject; human tissue; leukapheresis; neoplasm /cancer immunology; neoplasm /cancer vaccine; nonhuman therapy evaluation; ovary neoplasms; transfection; tumor antigens; vaccine development

DESCRIPTION (provided by applicant): Ovarian cancer, like many other types of cancers, presents a paradox: the coexistence of tumor cells and tumor-specific T cells, indicating that a disconnect exists between the afferent and efferent arms of the immune system. However, the tumor-specific immune response in ovarian cancer is not wholly ineffective, as the presence of intratumoral T cells correlated with increased progression-free or overall survival. We hypothesize that tumor immunotherapy will complement existing ovarian cancer therapies and provide long-term disease-free survival. The current gold standard in tumor immunotherapy is dendritic cell (DC)-based tumor vaccines. However, the DC-based vaccine field is faced with major unresolved issues, including the high cost of DC preparation, batch-to-batch variability, and poor yields from in vitro culture. For these reasons, we have focused on development of genetically modified tumor cell-based vaccines. The advantages of this approach include MHC Class l-restricted presentation of the complete tumor antigen repertoire, and in the case of established tumor cell lines, an unlimited supply of vaccine material. As a foundation for this work, we have generated 14 cell lines from primary ovarian tumors, as well as banking lymphocytes from the peripheral blood and tumor environment. Thus, we have the resources to study tumor cell-based vaccines in a completely autologous setting. The central hypothesis underlying our work is that tumor cells can be converted into professional antigen-presenting cells, capable of directly activating and arming tumor-specific T cells. We will test the hypotheses underlying our strategy through performing the following Specific Aims: 1) Identify candidate ovarian cancer cell lines that will serve as the foundation for our vaccine, and modifying them to function as Antigen Presenting Tumor Cells (APTCs) by transducing them with lentiviral vectors encoding CD83, CD86, 4-1BBL, IL-7, IL-15, and CCL21. 2) Examine the ability of APTCs to induce tumor-specific cytotoxic CD8+ cell responses in vitro. 3) Test APTC function in vivo in a beta2-microglobulin(null)/NOD//scid mouse model, in both adoptive transfer and active immunization settings. Successful completion of these studies will yield information pertinent to the mechanisms underlying tumor vaccines, leading to improved subsequent vaccine generations. Furthermore, these studies will provide the foundation for conducting a clinical trial.

描述（由申请人提供）：与许多其他类型的癌症一样，卵巢癌也呈现悖论：肿瘤细胞和肿瘤特异性T细胞的共存，表明免疫系统的传入和传播臂之间存在断开连接。然而，卵巢癌中肿瘤特异性的免疫反应并非完全无效，因为存在肿瘤内T细胞与无进展或总生存率的增加相关。我们假设肿瘤免疫疗法将补充现有的卵巢癌疗法并提供长期无疾病的生存。肿瘤免疫疗法的当前金标准是基于树突状细胞（DC）的肿瘤疫苗。但是，基于DC的疫苗领域面临着主要的未解决的问题，包括DC制备的高成本，批处理变异性的变异性以及体外培养的产量差。由于这些原因，我们专注于开发基于肿瘤细胞的转基因疫苗。这种方法的优点包括对完整肿瘤抗原库的MHC类L限制性呈现，以及在已建立的肿瘤细胞系（无限量的疫苗材料供应）的情况下。作为这项工作的基础，我们从原发性卵巢肿瘤以及外周血和肿瘤环境中产生了14种细胞系。因此，我们有在完全自体环境中研究基于肿瘤细胞的疫苗的资源。我们工作的基本假设是，肿瘤细胞可以转化为专业的抗原呈递细胞，能够直接激活和武装肿瘤特异性T细胞。我们将通过执行以下特定目的来测试我们策略的基础假设：1）确定候选卵巢癌细胞系将作为我们的疫苗的基础，并通过用牙病毒载体用编码CD83，CD83，CD86，4-1BBl，cccl，cccd83，and cccd83，ccd83，ccd83，ccd83，ccd83，ccd83，i il il i il cd83，cd83，cd83，cd83，cd83，cd83，cd83，cd83，cd83，and和cc cd83，i il ccd83，cd83，and和ccy and cd83，i il ccd83，and和c，通过将它们作为抗原发挥作用。 2）检查APTC在体外诱导肿瘤特异性细胞毒性CD8+细胞反应的能力。 3）在beta2-microglobolin（null）/nod // scid鼠标模型中，在beta2-microglobolin（null）中测试APTC函数，在产物转移和主动免疫设置中。这些研究的成功完成将产生与肿瘤疫苗潜在机制有关的信息，从而改善了随后的疫苗世代。此外，这些研究将为进行临床试验提供基础。