IMMUNITY TO MELANOMA VIA DENDRITIC CELLS

通过树突状细胞对黑色素瘤产生免疫力

• 批准号: 6191790
• 负责人: Ralph Marvin Steinman
• 金额: $ 219.44万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6191790
• 关键词: dendritic cells; melanoma; neoplasm /cancer immunology

Revised Abstract: Human tumor immunology has been advanced by the identification of antigens and the corresponding tumor specific lymphocytes, particularly killer and helper T-cells. This program will exploit the dendritic cell [DC] to enhance presentation of melanoma antigens to T-cells, primarily in humans but also in mouse models. Our impetus is 3 fold: (1) DCs can be generated in large numbers ex vivo from different precursor populations; (2) MHC class I and II products on DCs can be charged with an array of tumor antigens by feeding apoptotic and necrotic cells; (3) antigen-bearing DCs can rapidly boost the human immune system in situ. Therefore an integrated program in Dallas and New York can begin to actively immunize patients to melanoma antigens, concommitant with laboratory studies to learn to enhance DC processing of tumor antigens, to evaluate the roles of distinct DC subsets and maturation states, and to observe DC function in tumors and lymph nodes in situ. This program emphasizes melanoma, because tumor-specific T-cells are known for mice and humans, and it is now evident that DCs can present in vitro melanoma antigens derived from apoptotic cells. Documentation of tumor-specific immunity in humans has become more accessible with quantitative assays that are in place and include: binding of MHC-tetramers, production of ELISPOTS, and recall assays to elicit specific killer T-cells. The program will include two dual center randomized trials. In the first we will compare two types of DC in eliciting immunity to melanoma peptides, and look for spreading of the immune response to other antigens, as an index of cross presentation in vivo. In the second, we will compare DCs loaded with peptides vs. dying tumor cells in expanding tumor specific CD4 and CD8 T-cells. Shared ongoing core facilities for administration, DC production, and immune monitoring will energize and standardize interactions. Together, we hypothesize that DCs, nature's adjuvant, will enhance immunity to tumor antigens so that the clinical consequences for cancer vaccination and therapy can be pursued. COLLABORATING INSTITUTION(S) Arizona Cancer Center, Tucson, Arizona Baylor Research Institute, Dallas, Texas Institute Curie, Paris, France Memorial Sloan Kettering Cancer Center, New York, New York University of Texas, Southwestern Medical Center, Dallas, Texas.

修订后的摘要：通过识别抗原和相应的肿瘤特异性淋巴细胞，特别是杀伤性 T 细胞和辅助性 T 细胞，人类肿瘤免疫学取得了进步。该计划将利用树突状细胞 [DC] 来增强黑色素瘤抗原向 T 细胞的呈递，主要是在人类中，但也在小鼠模型中。我们的推动力有三方面：（1）可以从不同的前体群体离体大量产生树突状细胞（DC）； (2) DC上的MHC I类和II类产物可以通过喂养凋亡和坏死细胞来携带一系列肿瘤抗原； (3)携带抗原的DC可以快速原位增强人体免疫系统。因此，达拉斯和纽约的一项综合计划可以开始主动对患者进行黑色素瘤抗原免疫，同时进行实验室研究，以学习增强 DC 对肿瘤抗原的处理，评估不同 DC 子集和成熟状态的作用，并观察 DC 功能在原位肿瘤和淋巴结中。该计划强调黑色素瘤，因为小鼠和人类都知道肿瘤特异性 T 细胞，而且现在很明显 DC 可以在体外呈递源自凋亡细胞的黑色素瘤抗原。通过现有的定量测定，人类肿瘤特异性免疫的记录变得更加容易，这些测定包括：MHC 四聚体的结合、ELISPOTS 的产生以及引发特异性杀伤 T 细胞的回忆测定。该计划将包括两项双中心随机试验。首先，我们将比较两种类型的 DC 在引发对黑色素瘤肽的免疫方面的情况，并寻找对其他抗原的免疫反应的传播，作为体内交叉呈递的指标。 在第二部分中，我们将在扩增肿瘤特异性 CD4 和 CD8 T 细胞时比较负载肽的 DC 与垂死的肿瘤细胞。用于管理、DC 生产和免疫监控的共享持续核心设施将激励和标准化交互。我们共同假设，树突状细胞（DC）作为天然佐剂，将增强对肿瘤抗原的免疫力，从而可以追求癌症疫苗接种和治疗的临床效果。合作机构 亚利桑那州图森市亚利桑那癌症中心 德克萨斯州达拉斯市贝勒研究所 法国巴黎居里研究所 纽约纪念斯隆凯特琳癌症中心、纽约州德克萨斯大学、德克萨斯州达拉斯市西南医学中心。