IMMUNITY TO MELANOMA VIA DENDRITIC CELLS

修订摘要：通过鉴定抗原和相应的肿瘤特异性淋巴细胞，特别是杀伤和辅助T细胞，人类肿瘤免疫学已经得到了发展。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，主要在人类中，但也在小鼠模型中。我们的动力是三重的：（1）DC可以从不同的前体群体离体大量产生;（2）DC上的MHC I类和II类产物可以通过饲养凋亡和坏死细胞而被加载有一系列肿瘤抗原;（3）携带抗原的DC可以原位快速增强人免疫系统。因此，在达拉斯和纽约的一个综合项目可以开始主动免疫患者黑色素瘤抗原，与实验室研究相一致，以学习增强DC对肿瘤抗原的加工，评估不同DC亚群和成熟状态的作用，并原位观察DC在肿瘤和淋巴结中的功能。该项目强调黑色素瘤，因为已知小鼠和人类的肿瘤特异性T细胞，现在很明显，DC可以在体外呈递来自凋亡细胞的黑色素瘤抗原。人类肿瘤特异性免疫的记录已经变得更容易与定量测定，包括：MHC-四聚体的结合，ELISPOTS的生产，并召回测定，以引发特定的杀伤T细胞。该项目将包括两项双中心随机试验。在第一，我们将比较两种类型的DC在引发免疫黑色素瘤肽，并寻找其他抗原的免疫反应的传播，作为在体内交叉呈递的指标。 在第二部分中，我们将比较负载有肽的DC与垂死的肿瘤细胞在扩增肿瘤特异性CD 4和CD 8 T细胞方面的差异。用于管理、DC生产和免疫监测的共享持续核心设施将激发和标准化相互作用。总之，我们假设DC，自然界的佐剂，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结果。合作机构（S）亚利桑那州图森市亚利桑那州癌症中心贝勒研究所，达拉斯，得克萨斯州居里研究所，法国巴黎纪念斯隆凯特琳癌症中心，纽约，纽约得克萨斯大学西南医学中心，得克萨斯州达拉斯。

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.