DENDRITIC CELL THERAPIES ELICIT EFFECTIVE ANTITUMOR RESPONSES

鉴于在鉴定、分离和培养方面的最新进展 人树突状细胞，很可能在临床试验中过继使用 被转移的细胞将在下一阶段发挥重要作用 过继免疫治疗的发展。与此相关的主要问题 目前的采用疗法(主要局限于 黑色素瘤和肾癌患者)是他们利用T- 从肿瘤部位扩增出来的细胞 效果不佳。发展新的T细胞(和潜在的B细胞)反应性 肿瘤是DC策略的主要目标。我们设计了一种临床 人类白细胞抗原A2+黑色素瘤患者外周血 血源性树突状细胞与GM-CSF和IL-4共同培养5-7天， 用从最近提取的合成黑色素瘤多肽脉冲 鉴定了MART1/Melan A、gp100或酪氨酸酶蛋白。更有问题的是， 而这一应用的主要焦点一直是肿瘤的起源 相关T细胞表位尚未确定的肿瘤抗原 已确定并适用于人类白细胞抗原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 天然抗原的类型-在体外用细胞因子或 热，或途径，方法，和类型的天然抗原的体外跟踪 用细胞因子或热处理，或在遗传 修饰)，以及适当的细胞因子刺激。此外， 有关儿童外周血中树突状细胞状况的信息 癌症患者树突状细胞功能障碍的可能性与 肿瘤部位的因素，最佳部位，最佳方法 体内扩增细胞治疗与临床功能障碍相关的因素 肿瘤部位及临床应用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。我们会 执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：目标一。 决定在癌症患者中调查这些问题。我们会 开发有效的方法来获得和传递肿瘤抗原肽或 自体树突状细胞诱导肿瘤特异性T细胞的蛋白质 癌症患者。目的II.使用基因修饰来增强功能 通过细胞因子或肿瘤的表达过继转移DC 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.