IMMUNITY TO MELANOMA VIA DENDRITIC CELLS

人类肿瘤免疫学通过识别抗原和相应的肿瘤特异性淋巴细胞，特别是杀伤T细胞和辅助T细胞而得到发展。该计划将利用树突状细胞[DC]来增强黑色素瘤抗原对T细胞的呈递，主要是在人类中，但也在小鼠模型中。我们的动力有3个方面：(1)不同前体细胞在体外可以大量生成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可以快速增强人体原位免疫系统。因此，达拉斯和纽约的综合计划可以开始积极免疫患者对黑色素瘤抗原，结合实验室研究，学习加强肿瘤抗原的DC处理，评估不同的DC亚群和成熟状态的作用，并原位观察肿瘤和淋巴结中的DC功能。这个项目强调黑色素瘤，因为肿瘤特异性T细胞对小鼠和人类都是已知的，而且现在很明显，树突状细胞可以在体外呈现来自于凋亡细胞的黑色素瘤抗原。随着定量分析的到位，对人类肿瘤特异性免疫的记录变得更加容易，包括：MHC-四聚体的结合，ELISPOTS的产生，以及激发特异性杀伤T细胞的召回试验。该计划将包括两个双中心随机试验。首先，我们将比较两种类型的DC在诱导对黑色素瘤多肽的免疫方面的差异，并寻找对其他抗原的免疫反应的扩散，作为体内交叉呈现的指标。在第二项研究中，我们将比较负载多肽的DC和濒临死亡的肿瘤细胞在扩增肿瘤特异性CD4和CD8T细胞方面的差异。共享的用于管理、DC生产和免疫监测的持续核心设施将为交互提供能量并使其标准化。总之，我们假设树突状细胞，自然的佐剂，将增强对肿瘤抗原的免疫力，从而可以追求癌症疫苗和治疗的临床后果。合作机构(S)亚利桑那州癌症中心，图森，亚利桑那州贝勒研究所，达拉斯，得克萨斯研究所居里，巴黎，法国纪念斯隆·凯特琳癌症中心，纽约，德克萨斯纽约大学，得克萨斯州达拉斯西南医学中心。

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.