GENETIC MODIFICATION OF HUMAN DENDRITIC CELLS FOR CANCER IMMUNITY

人类树突细胞的基因修饰以增强癌症免疫能力

基本信息

批准号：
7765556
负责人：
James William Young
金额：
$ 6.65万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7765556
关键词：
Address Adjuvant Adjuvanticity Alleles Antigen Presentation Antigens Area Autoantigens CD34 gene Chemicals Chimeric Proteins Coupling Cross Presentation Data Dendritic Cells Enzymes Epitopes Generations Genes Genetic Hematopoietic stem cells Human Immune Immune Tolerance Immune response Immunity In Vitro Langerhans cell Lead Link Lymphocyte Malignant Neoplasms Mediating Memory Methods Modeling Modification Molecular Mutation Myelogenous Natural Immunity Natural Killer Cells Plasmid Cloning Vector Property Proteins Public Health Regulatory T-Lymphocyte Residual Neoplasm Rest Retroviral Vector Series Small Interfering RNA Solutions T cell response T-Lymphocyte Testing Thinking Time Tryptophan 2,3 Dioxygenase Tumor Antigens adaptive immunity base cancer cell cytokine immunogenic improved inhibitor/antagonist interest melanoma methyl tryptophan novel strategies response vector

项目摘要

DESCRIPTION (provided by applicant): Advances in our understanding of human dendritic cells have resolved many important unknowns about the onset of innate and adaptive immunity and how dendritic cells could control these responses against cancer. Tumor antigens are poor immunogens by themselves, because they are either self or altered-self antigens. Hence the bar to overcoming tolerance toward cancer-self antigens, while attainable, is quite high. Dendritic cells can circumvent many of these barriers by presenting tumor antigens in association with all the other requisite molecules that elicit immune reactivity. Countervailing suppressor mechanisms involving indoleamine 2,3-dioxygenase (IDO) and mediated by regulatory lymphocytes must also be addressed, however. Genetic strategies offer advantages in coupling tumor antigens to dendritic cells. Multiple epitopes can be expressed, tailored to a variety of MHC alleles. Antigen-presentation is sustained over time, cytokines and other costimulatory molecules can be manipulated, and immune suppressor mechanisms can be altered. We will address these areas in a series of testable hypotheses using human Langerhans-type dendritic cells, genetically modified by retroviral or plasmid vectors to express melanoma antigens and other proteins of interest. We will introduce IL-12p70 by genetic alteration of Langerhans cells to stimulate and harness the adjuvant properties of natural killer (NK) cells. Novel approaches will also be tested for the sustained activation of Langerhans cells and improved cross-presentation of opsonized tumor antigen through transduced expression of the activating Fc-gamma Rll, CD32a. This will be tested in combination with gene-based IL-12p70-Fc fusion constructs to assess increased cytokine adjuvanticity. Genetic methods that interfere with suppressor mechanisms involving IDO and mediated by regulatory lymphocytes will be studied. The results of these studies should lead to improved, coordinate stimulation of innate and adaptive immunity against cancer by a single, genetically optimized dendritic cell. (Relevance to public health/Lay summary: Genetic alterations of specialized Langerhans-type dendritic cells will be tested and improved to increase immunity against cancer, using melanoma as the model. These approaches should find their greatest application in treating minimal residual disease after primary therapy.)

描述（由申请人提供）：我们对人类树突细胞的理解的进步已经解决了许多关于先天和适应性免疫发作的重要未知数，以及树突状细胞如何控制对癌症的这些反应。肿瘤抗原本身是不良的免疫原子，因为它们是自我或改变自身的抗原。因此，可以克服对癌症抗原的耐受性的标准虽然可以实现，却很高。树突状细胞可以通过与所有其他引起免疫反应性的其他必要分子相关的肿瘤抗原来规避这些障碍。但是，还必须解决涉及吲哚胺2,3-二氧酶（IDO）并由调节淋巴细胞介导的抑制抑制机制。遗传策略在将肿瘤抗原与树突状细胞耦合方面具有优势。可以表达多个表位，并根据各种MHC等位基因量身定制。随着时间的流逝，可以操纵抗原呈递，细胞因子和其他共刺激分子，并且可以改变免疫抑制机制。我们将使用人类兰格汉型树突状细胞中的一系列可检验的假设来解决这些区域，该假设通过逆转录病毒或质粒载体进行基因修饰，以表达黑色素瘤抗原和其他感兴趣的蛋白质。我们将通过Langerhans细胞的遗传改变来刺激和利用自然杀伤（NK）细胞的辅助性能来引入IL-12P70。新方法还将通过通过转导的激活FC-Gamma RLL的表达CD32A来测试兰格汉细胞持续激活的langerhans细胞的持续激活。这将与基于基因的IL-12P70-FC融合构建体结合进行测试，以评估细胞因子辅助性的增加。将研究干扰涉及IDO并由调节性淋巴细胞介导的抑制机制的遗传方法。这些研究的结果应导致通过单个遗传优化的树突状细胞改善，协调对先天性的刺激和适应性免疫。（与公共卫生/外行摘要有关：专门的兰格汉型树突状细胞的遗传改变将测试并改善以提高对癌症的免疫力，使用黑色素瘤作为模型。这些方法应在治疗初级治疗后最小残留疾病时发现其最大的应用。）