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

• 批准号: 7266455
• 负责人: James William Young
• 金额: $ 31.22万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266455
• 关键词: GENETIC; MODIFICATION; HUMAN; DENDRITIC; CELLS

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）：我们对人类树突状细胞理解的进步已经解决了关于先天性和适应性免疫的发生以及树突状细胞如何控制这些针对癌症的反应的许多重要的未知数。肿瘤抗原本身是较差的免疫原，因为它们要么是自身抗原，要么是改变的自身抗原。因此，克服对癌症自身抗原的耐受性的障碍虽然可以实现，但相当高。树突状细胞可以通过呈递肿瘤抗原以及引发免疫反应的所有其他必需分子来绕过许多这些屏障。然而，还必须解决涉及吲哚胺 2,3-双加氧酶 (IDO) 并由调节性淋巴细胞介导的对抗抑制机制。遗传策略在将肿瘤抗原与树突状细胞偶联方面具有优势。可以针对各种 MHC 等位基因表达多个表位。抗原呈递随着时间的推移而持续，细胞因子和其他共刺激分子可以被操纵，并且免疫抑制机制可以被改变。我们将使用人类朗格汉斯型树突状细胞通过一系列可测试的假设来解决这些领域的问题，这些细胞通过逆转录病毒或质粒载体进行基因改造，以表达黑色素瘤抗原和其他感兴趣的蛋白质。我们将通过朗格汉斯细胞的基因改造引入 IL-12p70，以刺激和利用自然杀伤 (NK) 细胞的佐剂特性。还将测试朗格汉斯细胞的持续激活以及通过激活性 Fc-gamma Rll、CD32a 的转导表达改善调理肿瘤抗原的交叉呈递的新方法。这将与基于基因的 IL-12p70-Fc 融合构建体结合进行测试，以评估增加的细胞因子佐剂作用。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。这些研究的结果应该可以通过单一的、基因优化的树突状细胞来改善、协调地刺激针对癌症的先天性和适应性免疫。 （与公共卫生的相关性/简单总结：将以黑色素瘤为模型，测试和改进专门的朗格汉斯型树突状细胞的遗传改变，以提高对癌症的免疫力。这些方法应该在初级治疗后治疗微小残留病方面找到最大的应用。）