IN VIVO GENERATED DENDRITIC CELL BASED IMMUNOTHERAPY

描述（由申请人提供）：财政支持和保护时间是 要求指导临床研究和正式课程工作的计划 获得临床研究硕士学位 这种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 位置 拟议的研究项目作为一种工具， 指导经验。 三位合作导师将批判性地评估 包括临床和体外实验。 的统一 拟议研究项目的目标是开发基于DC的 免疫疗法 这些项目的优势是两个新的第一阶段， 他们所经历的考验。 第一次展示了安全地 通过给予粒细胞巨噬细胞集落在体内产生DC 刺激因子（GM-CSF）联合白细胞介素4（IL-4）治疗 晚期癌症 这种方法取代了大量抽血， 参与DC的离体产生的加工。 临床证据 在CaP受试者中观察到获益。 第二次试验证明了安全性 和诱导对基因工程疫苗-牛痘病毒的免疫力 （VV）-MUC-1-IL-2在患有CaP和升高的前列腺特异性抗原（PSA）的男性中。 研究者假设GM-CSF加IL-4可以作为一种免疫抑制剂。 佐剂以增强对VV-MUC-1-IL-2疫苗的应答。 的产生 接种前体内DC将作为有效抗原的来源 将能够展示MUC-1的细胞呈递给免疫系统。 两个目标 将使用UCLA-一般临床研究的资源进行探索 中心（GCRC）：1）一项II期试验，旨在表征胃肠外 GM-CSF加IL-4治疗激素难治性CaP受试者;和2）I期 确定体内扩增DC的安全性和免疫效果的试验 在用VV-MUC-1-IL-2疫苗接种之前，在患有VV-MUC-1-IL-2的患者中， CaP和PSA升高。 这些研究的结果应该为 用于将体内产生的DC和基于肿瘤抗原的治疗应用于 各种癌症。 最终，这一建议是一个平台， 候选人寻求培训，以进一步在临床癌症研究， 肿瘤护理的翻译界面。 给予必要的支持， 持续这段时间的训练，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.