Multiple Tumor Antigen-loaded DC Vaccine for Hepatocellular Cancer

用于肝细胞癌的多种肿瘤抗原负载 DC 疫苗

基本信息

批准号：
8676457
负责人：
Lisa Helene Butterfield
金额：
$ 36.81万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676457
关键词：
Address Antibody Formation Antigen Presentation Antigen Presentation Pathway Antigens Area Basic Science Biological Markers CD4 Positive T Lymphocytes CD8B1 gene Cancer Center Cancer Patient Cell Maturation Cells Cessation of life Chronic Clinical Clinical Trials Cytoplasm Data Dendritic Cell Vaccine Dendritic Cells Doctor of Medicine Early Diagnosis Endosomes Enrollment Epitopes Explosion Fatigue Frequencies Future Health Hepatitis B Virus Hepatitis C Hepatitis C virus Histocompatibility Antigens Class I Human Immune Immune response Immunity Immunization Immunologic Monitoring Immunotherapy In Vitro Incidence Infection Inflammatory Interleukin-10 Interleukin-2 Interleukin-5 Intervention Knowledge Laboratories Lead Length Leukapheresis Logistics Longevity Lymphocyte Lymphocyte Activation MHC Class I Genes MHC Class II Genes Malignant Neoplasms Malignant neoplasm of liver Memory Mental Depression Minority Modeling Mus NK Cell Activation Natural Killer Cells Outcome Pain Patients Peptides Phase Phenotype Physiologic pulse Pinocytosis Plastics Preparation Primary carcinoma of the liver cells Process Proteins Protocols documentation Quality of life Reaction Time Regulatory T-Lymphocyte Research Resected Route Safety Serum Signal Transduction Signal Transduction Pathway Staging Staining method Stains Surface Survival Rate Symptoms T cell response T-Cell Activation T-Lymphocyte Testing Time Toxic effect Transgenes Translations Tumor Antigens Tumor Immunity Tumor Markers Tumor-Derived University of Pittsburgh Cancer Institute Vaccinated Vaccine Design Vaccines X-Ray Computed Tomography alpha-Fetoproteins antigen processing base cytokine design feeding glypican 3 granzyme B health related quality of life immune activation immunogenic improved in vivo mannose receptor melanoma novel vaccines oncofetal antigen palliative patient population pre-clinical preclinical study response success trafficking tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Our Central Hypothesis is that immunization of hepatocellular cancer (HCC) patients with a rationally-designed dendritic cell (DC)-based vaccine which presents HCC- associated tumor antigens AFP, glypican-3 and MAGE-A3 will result in activation of CD8+ and CD4+ T cells which recognize tumors. This broad, polyclonal, multi-antigen immunity will also activate NK cells and improve time to progression (TTP) and health-related quality of life (HRQL). We will test a DC vaccine differentially loaded with 3 defined antigens to promote broad immunity. DC will be protein-fed, adenovirally-transduced and peptide-pulsed. This will result in antigen presence in endosomes (from protein-fed antigen), in the cytoplasm (AdV-delivered antigen) and on the surface (peptide-pulsed). This setting will allow direct comparison of these three modes of antigen presentation from a single vaccine, and also allow for a comparison of vaccine-delivered CD4+ T cell help (AFP, GPC3) with direct CD8+ activation only (MAGE-A3) on the frequency changes, functional quality and longevity of the corresponding CD8+ T cells. A.1 Specific Aim 1. Antigen Processing and Presentation. In this aim, we will analyze the intracellular processing of the loaded antigens in HBV+/HCV+ HCC patient DC in a preclinical, in vitro, setting. We will address several mechanistic questions about the differentially loaded DC vaccines: mechanism of protein uptake; intracellular antigen localization; duration of antigen presence and presentation; the effect of DC maturation; and the signal transduction pathways activated. A.2 Specific Aim 2. Lymphocyte activation. In this aim, we will analyze the result of presentation of the full length antigens (AFP, GPC3) and MHC class I-restricted peptide epitopes in HCC patient DC. We will address: CD8+ and CD4+ T cell activation, their phenotype and their function; NK cell activation, and potential for regulatory T cell (Treg) activation or inhibition. A.3 Specific Aim 3. Phase I Pilot Clinical Trial. In this aim, we will enroll and vaccinate 20 AFP+ HCC patients with the multi-antigen loaded DC vaccine. A.4 Specific Aim 4. Immunological Assessment of Vaccine Responses. In this aim, we will characterize immune responses to vaccine-presented antigens; determine NK responses; test for serum tumor markers, biomarkers and Treg and test for correlation with immune and clinical responses. Rational design of vaccines, based on this new information should allow for more rational design of the immune activation to be achieved by newer vaccines.

描述（由申请人提供）：我们的中心假设是，使用合理设计的基于树突状细胞（DC）的疫苗对肝细胞癌（HCC）患者进行免疫接种，该疫苗呈现 HCC 相关肿瘤抗原 AFP、磷脂酰肌醇蛋白聚糖-3 和 MAGE-A3导致识别肿瘤的 CD8+ 和 CD4+ T 细胞的激活。这种广泛、多克隆、多抗原的免疫还将激活 NK 细胞并改善进展时间 (TTP) 和健康相关的生活质量 (HRQL)。我们将测试一种差异载有 3 种确定抗原的 DC 疫苗，以促进广泛免疫。 DC将被蛋白喂养、腺病毒转导和肽脉冲。这将导致抗原在内体（来自蛋白质喂养的抗原）、细胞质（AdV 递送的抗原）和表面（肽脉冲）中存在。此设置将允许直接比较单一疫苗的这三种抗原呈递模式，并且还允许比较疫苗递送的 CD4+ T 细胞帮助（AFP、GPC3）与仅直接 CD8+ 激活（MAGE-A3）的频率相应 CD8+ T 细胞的变化、功能质量和寿命。 A.1 具体目标 1. 抗原加工和呈现。为此，我们将在临床前体外环境中分析 HBV+/HCV+ HCC 患者 DC 中负载抗原的细胞内加工。我们将解决有关差异负载 DC 疫苗的几个机制问题：蛋白质摄取机制；细胞内抗原定位；抗原存在和呈递的持续时间； DC成熟的影响；并且信号转导途径被激活。 A.2 具体目标 2. 淋巴细胞激活。为此，我们将分析 HCC 患者 DC 中全长抗原（AFP、GPC3）和 MHC I 类限制性肽表位的呈递结果。我们将讨论：CD8+ 和 CD4+ T 细胞的激活、它们的表型和功能； NK 细胞激活，以及调节性 T 细胞 (Treg) 激活或抑制的潜力。 A.3 具体目标 3. I 期试点临床试验。为此，我们将招募 20 名 AFP+ HCC 患者并为其接种多抗原 DC 疫苗。 A.4 具体目标 4. 疫苗反应的免疫学评估。为此，我们将表征对疫苗呈递抗原的免疫反应；确定 NK 反应；检测血清肿瘤标志物、生物标志物和 Treg，并检测与免疫和临床反应的相关性。基于这一新信息的疫苗合理设计应该允许通过新疫苗实现更合理的免疫激活设计。