IN VIVO GENERATED DENDRITIC CELL BASED IMMUNOTHERAPY

描述(由申请人提供)：经济支持和保护时间为 申请指导临床研究和正规课程工作的计划 获得临床研究硕士学位。这段受保护和指导的时间 是高度目标导向的学术独立和终身教职员工 位置。拟议的研究项目是一种工具，可以从中获益 有指导的体验。三位合作导师将进行批判性评估 这些项目的临床和体外部分。一元化 拟议研究项目的目标是开发以DC为基础的 免疫疗法。这些项目的优点是两个新颖的第一阶段 他们所经历的考验。第一个证明有能力安全地 粒细胞-巨噬细胞集落体内诱导树突状细胞 刺激因子(GM-CSF)联合白介素4(IL-4)对慢性阻塞性肺疾病患者的影响 晚期癌症。这种方法取代了大量抽血和 处理过程涉及到体外产生DC。临床证据 在有CAP的受试者中注意到了益处。第二次试验证明是安全的。 以及对一种基因工程疫苗--痘苗病毒的免疫诱导 前列腺特异性抗原(PSA)升高的CAP患者的(VV)-MUC-1-IL-2。 研究人员推测，GM-CSF和IL-4可以作为一种 佐剂以增强对VV-MUC-1-IL-2疫苗的应答。新一代人 接种前体内的DC将作为有效抗原的来源 将能够展示MUC-1的细胞呈现给免疫系统。两个目标 将利用加州大学洛杉矶分校-普通临床研究的资源进行探索 中心(GCRC)：1)第二阶段试验，以表征静脉注射的疗效 激素难治性帽子患者的GM-CSF+IL-4；2)A期 体内扩增树突状细胞安全性和免疫学效应的研究 慢性粒细胞白血病患者接种VV-MUC-1-IL-2前联合应用GM-CSF和IL-4 上限和不断上升的PSA。这些研究的结果应该提供基础 将体内产生的DC和基于肿瘤抗原的治疗应用于 各种癌症。归根结底，这项提案是一个平台， 候选人寻求培训，以进一步在临床和癌症研究 肿瘤学护理的翻译界面。鉴于有必要的支持， 坚持这段时间的训练，个人动力的结合， 经验丰富的导师和机构资源将确保成功。

DESCRIPTION (provided by applicant): Financial support and protected time is requested for a program of mentored clinical research and formal course work leading to a Master's in Clinical Research. This protected and mentored time is highly goal-oriented towards academic independence and a tenured faculty position. The proposed research project serves as a tool from which to gain mentored experience. Three collaborating mentors will critically evaluate both the clinical and in vitro components of the projects. The unifying objectives of the proposed research projects are to develop DC-based immunotherapy. The strengths of these projects are the two novel Phase I trials from which they arise. The first demonstrating the ability to safely generate DC in vivo by the administration of granulocyte macrophage-colony stimulating factor (GM-CSF) plus interleukin 4 (IL-4) in subjects with advanced cancer. This approach supersedes the large blood draws and processing involved in the ex vivo generation of DC. Evidence of clinical benefit was noted in subjects with CaP. The second trial demonstrated safety and induction of immunity to a genetically engineered vaccine - Vaccinia Virus (VV)-MUC-1-IL-2 in men with CaP and a rising prostate-specific antigen (PSA). The investigators hypothesized that GM-CSF plus IL-4 could be used as an adjuvant to enhance response to the VV-MUC-1-IL-2 vaccine. The generation of DC in vivo prior to vaccination will serve as a source of potent antigen presenting cells capable of displaying MUC-1 to the immune system. Two aims will be explored using the resources of the UCLA-General Clinical Research Center (GCRC): 1) a Phase II trial to characterize the efficacy of parenteral GM-CSF plus IL-4 in subjects with hormone refractory CaP; and 2) a Phase I trial to determine the safety and immunologic effects of expanding DC in vivo with GM-CSF and IL-4, prior to vaccination with VV-MUC-1-IL-2 in patients with CaP and a rising PSA. Outcomes from these studies should provide the basis for applying in vivo generated DC and tumor antigen-based treatment to a variety of cancers. Ultimately, this proposal is a platform from which the candidate seeks training to further cancer research at the clinical and translational interface of oncologic care. Given the support necessary to sustain this period of training, the combination of personal drive, experienced mentors and institutional resources will assure success.