Development of tumor based antigen presenting cells

基于肿瘤的抗原呈递细胞的开发

• 批准号: 7228082
• 负责人: James L Riley
• 金额: $ 26.22万
• 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/7228082
• 关键词: 5-(6)-carboxyfluorescein diacetate succinimidyl ester; Abbreviations; Accounting; Active Immunization; Adoptive Transfer; Antigen Presentation; Antigen-Presenting Cells; Antigens; Autologous; Biological Assay; CCL21 gene; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cancer cell line; Cell Line; Cell physiology; Cells; Class; Clinical Trials; Complement; Complex; Consensus; Cross Presentation; Cytomegalovirus; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Disease-Free Survival; Engineering; Environment; Esters; Foundations; Generations; Genes; Gold; Human; Immune; Immune response; Immune system; Immunotherapy; In Vitro; Interleukin-15; Interleukin-7; Internal Ribosome Entry Site; Laboratories; Lentivirus Vector; Maintenance; Malignant neoplasm of ovary; Measures; Mediating; Modeling; Monoclonal Antibodies; Mus; Numbers; Peripheral Blood Lymphocyte; Research Personnel; Resources; Serum; Signal Pathway; Standards of Weights and Measures; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Tumor Antigens; Tumor Cell Line; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Upper arm; Vaccines; Work; autologous lymphocytes; base; cancer therapy; cancer type; carboxyfluorescein; cell preparation; cost; cytokine; cytotoxic; fetal; immunogenicity; improved; in vivo; intraperitoneal; killings; mouse model; neoplastic cell; ovarian neoplasm; response; subcutaneous; theories; tumor

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）：卵巢癌与许多其他类型的癌症一样，存在一个悖论：肿瘤细胞和肿瘤特异性 T 细胞共存，表明免疫系统的传入臂和传出臂之间存在脱节。然而，卵巢癌中的肿瘤特异性免疫反应并非完全无效，因为瘤内 T 细胞的存在与无进展生存期或总生存期的增加相关。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病生存。目前肿瘤免疫治疗的黄金标准是基于树突状细胞（DC）的肿瘤疫苗。然而，基于 DC 的疫苗领域面临着尚未解决的重大问题，包括 DC 制备成本高、批次间差异以及体外培养产量低等。出于这些原因，我们专注于开发基于转基因肿瘤细胞的疫苗。这种方法的优点包括完整肿瘤抗原库的 MHC I 类限制性呈递，以及在已建立的肿瘤细胞系的情况下，无限量供应疫苗材料。作为这项工作的基础，我们从原发性卵巢肿瘤中产生了 14 种细胞系，并从外周血和肿瘤环境中储存了淋巴细胞。因此，我们有资源在完全自体环境中研究基于肿瘤细胞的疫苗。我们工作的核心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具体目标来测试我们策略的假设：1) 鉴定候选卵巢癌细胞系，作为我们疫苗的基础，并通过用编码 CD83、CD86、4-1BBL、IL-7、IL-15 和 CCL21 的慢病毒载体。 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) 在过继转移和主动免疫环境下，在 beta2-微球蛋白（无效）/NOD//scid 小鼠模型中测试体内 APTC 功能。这些研究的成功完成将产生与肿瘤疫苗潜在机制相关的信息，从而改进后续的疫苗世代。此外，这些研究将为进行临床试验奠定基础。