Langerhans vs monocyte-derived dendritic cell vaccines

描述（由申请人提供）：这是一项I期试验，其中负载对照抗原和合成肿瘤衍生肽的自体人树突状细胞（DC）将用于确定体内安全性和毒性，并测试黑素瘤患者中T细胞介导的免疫力的产生。 AJCC III期或IV期疾病患者将有资格参加。 树突细胞的富集群体将作为来自CD 34+祖细胞的朗格汉斯细胞（LC）离体产生，或作为来自塑料粘附的外周血单核细胞的单核细胞衍生的树突细胞（moDC）离体产生。 将比较这两种不同类型的树突状细胞在体外扩增、成熟和Ag负载后，在体内皮内注射时的安全性、毒性和疫苗接种效力。 将招募3-6名患者的队列，并在研究的1a期部分交替入组，以仅使用两种类型的树突状细胞中的一种接受疫苗接种，例如，CD 34 + HPC衍生的朗格汉斯细胞（LD）或血液单核细胞衍生的树突状细胞（moDC）。 剂量递增将在患者组之间进行，而不是在单个患者内进行。 每个队列的累积将基于剂量限制性毒性或缺乏剂量限制性毒性。 在1a期确定DC的最佳生物剂量和类型后，本试验的1b期将增加9例额外患者。 反应评估将基于树突状细胞疫苗接种前后测量的T细胞功能和频率的变化（例如，在ELISPOT测定、T细胞增殖测定、四聚体频率和51 Cr-释放CTL测定中测量的细胞因子分泌）。 接种疫苗本身的DTH反应也将在初次和加强免疫接种后进行监测，并可选择进行皮肤活检。 将根据标准NCI毒性标准评估治疗的毒性。 除了已经构成该恶性肿瘤和疾病分期患者标准治疗的临床测量或结局评估外，本研究不需要额外的临床测量或结局评估。 我们预计在1a期招募18-36例患者，在1b期招募9例患者，总共招募27-45例患者。 我们预计每月约有2例患者的增加率。 本研究预计将在24个月内完成，具体取决于1a期试验中观察到的毒性。

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.