Langerhans vs monocyte-derived dendritic cell vaccines

描述（由申请人提供）：这是一项I期试验，其中自体人树突状细胞（dc）装载对照抗原和合成肿瘤衍生肽，将用于确定体内安全性和毒性，并测试黑色素瘤患者T细胞介导免疫的产生。患有AJCC III期或IV期疾病的患者将符合条件。丰富的树突状细胞群体将在体外产生，作为来自CD34+祖细胞的朗格汉斯细胞（LCs），或来自塑料粘附的外周血单个核细胞的单核细胞衍生的树突状细胞（moDCs）。这两种不同类型的树突状细胞将在体外扩增、成熟和体内皮内注射后进行安全性、毒性和疫苗接种效果的比较。3-6名患者的队列将在研究的1a期部分交替招募，仅使用两种类型的树突状细胞中的一种接种疫苗，例如CD34+ hpc衍生的朗格汉斯细胞（LDs）或血单核细胞衍生的树突状细胞（moDCs）。剂量增加将发生在患者组之间，而不是在单个患者体内。每个队列的应计金额将基于剂量限制性毒性或缺乏剂量限制性毒性。在确定1a期的最佳生物剂量和DC类型后，将增加9名患者进入该试验的1b期。反应评估将基于树突状细胞接种前后T细胞功能和频率的变化（例如，在ELISPOT测定中测量细胞因子分泌，T细胞增殖测定，四聚体频率和51cr释放CTL测定）。在初次免疫和加强免疫后，也将监测DTH对疫苗接种本身的反应，并可选择进行皮肤活检。治疗的毒性将根据NCI毒性标准进行评估。除了已经构成该恶性肿瘤和疾病阶段患者标准护理的那些临床测量或结果评估之外，本研究不需要其他临床测量或结果评估。我们预计在1a期累积18-36例患者，在1b期累积9例患者，总计27-45例患者。我们预计每月约有2例患者。该研究预计将在24个月内完成，具体时间取决于1a期观察到的毒性。

DESCRIPTION (provided by applicant): This is a Phase I trial in which autologous human dendritic cells (DCs), loaded with control antigens and synthetic tumor-derived peptides, will be used to define safety and toxicity in vivo, and to test for the generation of T cell mediated immunity in patients with melanoma. Patients with AJCC stage III or IV disease will be eligible. Enriched populations of dendritic cells will be generated ex vivo as Langerhans cells (LCs) from CD34+ progenitors, or as monocyte-derived dendritic cells (moDCs) from plastic-adherent, peripheral blood mononuclear cells. These two distinct types of dendritic cells will be compared for safety, toxicity, and vaccination efficacy after in vitro expansion, maturation, and Ag loading, when injected intradermally in vivo. Cohorts of 3-6 patients will be recruited and enrolled alternately in the phase 1a component of the study, to receive vaccinations using only one of two types of dendritic cells, e.g., CD34+ HPC-derived Langerhans cells (LDs) or blood monocyte-derived dendritic cells (moDCs). Dose escalations will occur between groups of patients, rather than within a single patient. Accrual per cohort will be based on dose limiting toxicities or lack thereof. Upon determination of the optimal biologic dose and type of DC in phase 1a, 9 additional patients will be accrued to phase 1b of this trial. Response assessments will be based on changes in T cell function and frequencies measured before and after dendritic cell vaccinations (e.g., cytokine secretion measured in ELISPOT assay, T cell proliferation assay, tetramer frequency, and 51Cr-release CTL assays). DTH reactions to the vaccinations themselves will also be monitored after primary and booster immunizations, with the option to perform skin biopsies. Toxicity of the treatment will be assessed according to standard NCI toxicity criteria. No additional clinical measurements or outcome assessments will be required as part of this research study beyond those that already constitute standard care for patients with this malignancy and stage of disease. We expect to accrue 18-36 patients in phase 1a and 9 patients in phase 1b for a total of 27-45 patients. We expect an accrual rate of approximately 2 patients per month. This study is expected to be completed within 24 months, depending on the toxicity observed in phase 1a.