Cyclin B-1 As a Tumor-specific Antigen in Oral Carcinoma

描述：本计划项目补助金的目标 (PPG)继续开发新疫苗接种策略， 鳞状细胞癌（OSCC）4年前开始。目前的竞争 延长申请是基于在各方面取得的重大进展， 疫苗开发过程，包括新抗原的发现， 辅助和细胞毒性T细胞对野生型序列（wt）p53表位应答， 肿瘤表位特异性T细胞的频率的测定 口腔鳞状细胞癌患者的外周循环，并了解 苦参碱介导的免疫效应细胞保护作用及其机制 负责肿瘤中T细胞对凋亡的敏感性 环境自体树突状细胞疫苗的临床试验 细胞（DC）和凋亡肿瘤细胞（ATC）在晚期OSCC患者中的表达， 仍在进行中。在过去四年中获得的知识的基础上，我们 现在计划扩大该计划的翻译方面， 候选疫苗表位的初步临床试验。研究来 实现这一目标将包括候选人的临床前评估 辅助表位和细胞毒性表位单独和一起用于免疫原性， 使用从正常供体和OSCC患者获得的T细胞; 肿瘤中含表位蛋白的过表达; 表位特异性T细胞的频率，使用四聚体和ELISPOT， 口腔鳞状细胞癌患者的循环和这些T细胞的能力， 自体DC上呈递的天然和/或合成抗原表位。到 提高潜在疫苗的效力、肿瘤细胞对 将评估免疫细胞并制定策略来克服或减少 这种抵抗。利用我们的发现， 口腔鳞状细胞癌细胞周期蛋白B1的表达是p53依赖性的，p53的临床前模型 基因敲除小鼠会自发产生肿瘤， 细胞周期蛋白B1疫苗的保护和治疗作用。这 将使我们能够评估细胞周期蛋白B1及其肽作为预防性疫苗。 治疗目标包括对口腔鳞状细胞癌患者进行试点疫苗接种试验， 随后在程序中用优化的T细胞确定的抗原进行治疗。 NCI正在进行的DC/ATC试验和基于p53的疫苗接种试验将提供 用于测试对疫苗的免疫反应的样本。三个项目和 两个核心（组织采购/DC实验室和临床 支持/生物统计学）包括该方案。该项目有一个 长期目标是通过新的治疗方法提高口腔鳞癌患者的生存率， 疫苗接种策略。

DESCRIPTION: The goal of this Program Project Grant (PPG) is continue development of novel vaccination strategies for human oral squamous cell carcinoma (OSCC) initiated 4 years ago. The current competitive renewal application is based on considerable progress in all aspects of the vaccine development process, including new antigen discovery, generation of helper and cytotoxic T cell responses to wild-type sequence (wt) p53 epitopes, determination of the frequency of tumor epitope-specific T cells in the peripheral circulation of patients with OSCC, and insights into cytokine-mediated protection of immune effector cells as well as mechanisms responsible for the sensitivity of T cells to apoptosis in the tumor environment. A clinical trial of a vaccine composed of autologous dendritic cells (DC) and apoptotic tumor cells (ATC) in patients with advanced OSCC is still in progress. Building on the knowledge gained in the last four years, we now plan to expand translational aspects of the Program and to bring the candidate vaccine epitopes to a pilot clinical trial. Research necessary to accomplish this goal will include pre-clinical evaluation of the candidate helper and cytotoxic epitopes individually and together for immunogenicity, using T cells obtained from normal donors and patients with OSCC; studies of overexpression of epitope-containing proteins in the tumor; determination of the frequency of the epitope-specific T cells, using tetramers and ELISPOT, in the circulation of OSCC patients and the ability of these T cells to respond to the natural and /or synthetic antigenic epitopes presented on autologous DC. To increase efficacy of potential vaccines, mechanisms of tumor-cell resistance to immune cells will be evaluated and strategies developed to overcome or diminish this resistance. Taking advantage of our discovery that aberrant expression in OSCC of cyclin B1 protein is p53 dependent, a pre-clinical model in p53 knockout mice, which spontaneously develop tumors, will be used to study protective as well as therapeutic effects of cyclin B1-based vaccines. This will allow us to evaluate cyclin B1 and its peptides as prophylactic vaccines. Therapeutic goals include a pilot vaccination trial for patients with OSCC to be treated later in the program with the optimized T-cell defined antigen(s). The ongoing DC/ATC trial and p53-based vaccination trials at NCI will provide specimens for testing of immune responses to the vaccine. Three projects and two cores (Tissue Procurement/DC Laboratory and Clinical Support/Biostatistics) comprise the Program. This Program Project has a long-term objective of improving survival of OSCC patients through novel vaccination strategies.