DENDRITIC CELL THERAPIES ELICIT EFFECTIVE ANTITUMOR RESPONSES

鉴于最近在鉴定、分离和培养 人类树突状细胞，很可能是临床试验使用过继 转移的细胞将在下一阶段发挥重要作用， 过继免疫疗法的发展。相关的主要问题 目前的过继疗法（主要限于 患有黑色素瘤和肾细胞癌的患者）是他们利用T- 细胞从肿瘤部位扩增出来， 无效。开发新的T细胞（和潜在的B细胞）反应性， 肿瘤是基于DC的策略的主要目标。我们设计了一个临床 HLA-A2+黑色素瘤患者将接受外周血淋巴细胞移植的方案 用GM-CSF和IL-4培养血液来源的树突状细胞5-7天， 用合成的黑色素瘤肽脉冲， 鉴定的MART 1/Melan A、gp 100或酪氨酸酶蛋白。更麻烦的是， 这一应用的主要焦点是肿瘤的衍生 来自肿瘤的抗原，其中相关的T细胞表位尚未被 HLA-A2阴性的黑色素瘤患者。 未回答的问题是那些与肿瘤细胞数量有关的问题 所需的最佳交付策略（时间、路线、方法和 天然抗原类型--用细胞因子或 热或途径、方法和类型天然抗原体外追踪 用细胞因子或热操作，或随后进行遗传修饰。 修饰）和适当的细胞因子刺激。此外，委员会认为， 关于树突状细胞在外周血中的状态的信息， 癌症患者，树突状细胞功能障碍的可能性有关， 肿瘤部位的因素，最佳部位和最佳方法， 在体内扩增细胞，用于临床功能障碍相关因素， 肿瘤部位，以及用于临床的体内扩增细胞的最佳方法 试验（GM-CSF，IL-4，Flt-3L）需要澄清和定义。我们将 进行一系列旨在调查这些问题的研究， 癌症患者。我们将制定以下具体目标：AIM I。 决定在癌症患者中调查这些问题。我们将 开发衍生和递送肿瘤抗原肽的有效手段，或 自体树突状细胞诱导肿瘤特异性T细胞， 癌症患者。AIM II.使用基因改造来增强功能 通过表达细胞因子或肿瘤细胞， 抗原

Given the recent advances in identification, separation and culture of human dendritic cells, it is likely that clinical trials using adoptively transferred cells will play an important role during the next stages in the development of adoptive immunotherapy. The major problem associated with current adoptive therapies (which have been limited to predominantly patients with melanoma and renal cell carcinoma) is that they utilize T- cells which have been expanded from tumor sites where they are admittedly ineffective. Developing new T-cell (and potentially B-cell) reactivity to tumor is a major goal of DC-based strategies. We have designed a clinical protocol in which HLA-A2+ patients with melanoma will have peripheral blood derived dendritic cells cultured with GM-CSF and IL-4 for 5-7 days, pulsed with synthetic melanoma peptides derived from the recently identified MART1/Melan A, gp100, or tyrosinase proteins. More problematic, and the major focus of this application, has been the derivation of tumor antigens from tumors in which relevant T-cell epitopes have not been identified and for the HLA-A2 negative individuals with melanoma. Unanswered questions are those related to the number of tumor cells required, the optimum strategy for delivery (timing, route, method, and type of natural antigen-following in vitro manipulation with cytokines or heat, or route, method, and type of natural antigen-following in vitro manipulation with cytokines or heat, or subsequent to genetic modification), and the appropriate cytokine stimulation. Furthermore, information about the status of dendritic cells in the peripheral blood of cancer patients, the possibility of dendritic cell dysfunction related to factors at the tumor site, and the optimum site, and the optimum means to expand cells in vivo for clinical dysfunction related to factors at the tumor site, and the optimum means to expand cells in vivo for clinical trials (GM-CSF, IL-4, Flt-3L) need to be clarified and defined. We will perform a series of studies designed to investigate these issues in patients with cancer. We will develop the following specific aims: AIM I. Determine to investigate these issues in patients with cancer. We will develop effective means to derive and deliver tumor antigen peptide or proteins to autologous dendritic cells to elicit tumor-specific T-cells in cancer patients. AIM II. Use genetic modifications to enhance the function of adoptively transferred DC's by the expression of cytokines or tumor antigens.