AFP-Based Immunotherapy for Hepatocellular Carcinoma

基于 AFP 的肝细胞癌免疫疗法

• 批准号: 6938586
• 负责人: ANTONI RIBAS
• 金额: $ 12.69万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938586
• 关键词: Freund' s adjuvant; T lymphocyte; alpha fetoprotein; autologous transplantation; biomarker; cellular immunity; clinical research; clinical trial phase I; clinical trial phase II; dendritic cells; enzyme linked immunosorbent assay; genetically modified animals; hepatocellular carcinoma; human subject; human therapy evaluation; interleukin 4; laboratory mouse; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research; vaccine evaluation; vector vaccine

DESCRIPTION (provided by applicant): Hepatocelluar carcinoma (HCC) is a leading cause of cancer death worldwide. There are essentially no effective systemic therapies for this disease and relapses aider local therapies are very common. In previous work we have shown that both the murine and human T cell repertoires can recognize alpha fetoprotein (AFP)-derived peptide epitopes in the context of MHC. In a murine tumor model of genetic immunotherapy, AFP can serve as a tumor rejection antigen. In an extensive mapping of human AFP we have identified 4 immunodominant peptide epitopes in the context of HLA-A2.1. We have initiated a clinical trial testing their safety and immunogenicity. In this proposal, I request support to continue this translational research with two specific aims: AIM 1. AFP IMMUNOTHERAPY CLINICAL TRIALS FOR HCC. (1) AFP Peptide Dendritic Cell Trial. Patients with HCC whose tumors produce AFP and are HLA-A2.1 will be immunized, in a dose-escalation phase I/II trial, with dendritic cells (DC) pulsed with four immunodominant AFP peptides. The main goals are determination of safety and an optimal dose. Trial monitoring includes a careful immunological analysis, using ELISPOT and tetramer assays, to develop biomarkers of effective immunization for further clinical testing of our original hypothesis of the immunogenicity of AFP. (2) AFP-Engineered Dendritic Cell Trial. In this phase I/II trial, patients with AFP+ HCC will be immunized with autologous DC transduced with a recombinant adenovirus vector expressing human AFP. This is the most powerful means of antitumor AFP-based immunization in our preclinical models. Immunological monitoring will include the determination of T cell responses to immunodominant and subdominant epitopes. AIM 2. PRECLINICAL TESTING OF AFP DNA-BASED VACCINES. DNA-based vaccines can generate T cell responses and protective immunity and have clear practical advantages over DC-based vaccines. However, the levels of protection observed thus, far with AFP plasmid or AFP virus alone are inferior to gene-modified DC. I propose to use the same animal models that have allowed the development of the clinical trials in Aim 1 to test promising avenues aimed at enhancing the immune stimulatory ability of DNA-based vaccines. These approaches include the addition of a GM-CSF expression cassette, the use of Sindbis backbones, and/or boosting antigen-specific responses with replication incompetent viral vectors (prime-boost strategy). In summary, I propose a clinically-oriented research program that translates this original work into novel, evidence-based immnunotherapy trials for hepatocellular carcinoma.

描述（由申请人提供）： 肝细胞癌 (HCC) 是一种 全球癌症死亡的主要原因。基本上没有什么有效的办法 对于这种疾病的全身治疗和复发辅助局部治疗是 很常见。在之前的工作中，我们已经证明小鼠和人类 T 细胞库可以识别甲胎蛋白 (AFP) 衍生的肽 MHC 背景下的表位。在小鼠遗传性肿瘤模型中 免疫疗法中，AFP可以作为肿瘤排斥抗原。在广泛的 通过对人类 AFP 的作图，我们鉴定出了 4 个免疫显性肽表位 HLA-A2.1 的背景。我们已经启动了一项临床试验来测试他们的 安全性和免疫原性。在本提案中，我请求支持以继续 这项转化研究有两个具体目标： 目标 1. AFP 免疫治疗 HCC 临床试验。 (1) AFP 肽树突状 细胞试验。其肿瘤产生 AFP 且为 HLA-A2.1 的 HCC 患者将 在剂量递增的 I/II 期试验中，使用树突状细胞 (DC) 进行免疫接种 用四种免疫显性 AFP 肽进行脉冲。主要目标是决心 安全性和最佳剂量。试验监控包括仔细 使用 ELISPOT 和四聚体测定进行免疫学分析，以开发 有效免疫的生物标志物，用于我们的进一步临床测试 AFP 免疫原性的最初假设。 (2) AFP 设计 树突状细胞试验。在此 I/II 期试验中，AFP+ HCC 患者将被 用重组腺病毒载体转导的自体 DC 进行免疫 表达人类 AFP。这是基于AFP的最有力的抗肿瘤手段 我们的临床前模型中的免疫接种。免疫学监测将包括 确定 T 细胞对免疫优势和次优势的反应 表位。 目标 2. AFP DNA 疫苗的临床前测试。基于 DNA 的疫苗可以 产生T细胞反应和保护性免疫，具有明确的实用性 与 DC 疫苗相比的优势。然而，观察到的保护水平 因此，到目前为止，单独使用 AFP 质粒或 AFP 病毒不如基因修饰的 直流。我建议使用与开发相同的动物模型 目标 1 中的临床试验旨在测试有希望的途径，旨在增强 DNA疫苗的免疫刺激能力。这些方法 包括添加 GM-CSF 表达盒、使用 Sindbis 骨架，和/或通过复制增强抗原特异性反应 不合格的病毒载体（初免-加强策略）。 总之，我提出了一个以临床为导向的研究计划，该计划将 这项原创工作涉及新颖的、基于证据的免疫治疗试验 肝细胞癌。