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：
7780252
负责人：
Lisa Helene Butterfield
金额：
$ 26.74万
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 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7780252
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 public health relevance 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. PUBLIC HEALTH RELEVANCE: Globally, there are at least 600,000 new cases of hepatocellular cancer each year, over 21,000 new cases in the U.S. and over 18,000 deaths from hepatocellular cancer (HCC) in the U.S. annually. The incidence of HCC has risen in the last several decades, (due to increased HCV infection in the U.S.) and the 5-year survival rate is only 2-8%. Most therapies are only palliative due to lack of early detection. Therefore, the incidence of HCC continues to rise, and will become an even greater health problem for the next half century.

描述（由申请人提供）：我们的中心假设是，肝细胞癌（HCC）患者的免疫具有合理设计的树突状细胞（DC）基于HCC-相关的肿瘤抗原AFP，Glypican-3和Mage-A3的疫苗将导致CD8+和CD4+ T tumors的活性。这种广泛的多克隆，多抗原免疫也将激活NK细胞并改善进展的时间（TTP）和与健康相关的生活质量（HRQL）。我们将测试用3种定义的抗原差异加载的DC疫苗，以促进广泛的免疫力。 DC将是蛋白质喂养的，腺病毒转导的和肽粉的。这将导致抗原存在于内体（来自蛋白质食用抗原），细胞质（Adved抗原）和表面（肽脉冲）中的抗原。该设置将允许从单个疫苗中直接比较这三种模式的抗原表现，还可以在频率变化，功能质量和寿命上，将疫苗传递的CD4+ T细胞帮助（AFP，GPC3）与仅直接CD8+激活（MAGE-A3）进行比较。 A.1具体目的1。抗原加工和表现。在此目标中，我们将分析HBV+/HCV+ HCC患者DC中临床前的体外设置中负载抗原的细胞内加工。我们将解决有关差分负载的直流疫苗的几个机械问题：蛋白质摄取的机理；细胞内抗原定位；抗原存在和表现的持续时间； DC成熟的影响；并激活了信号转导途径。 A.2特定目标2。淋巴细胞激活。在此目标中，我们将分析HCC患者DC中全长抗原（AFP，GPC3）和I类限制性肽表位的结果。我们将解决：CD8+和CD4+ T细胞激活，它们的表型及其功能； 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。在此目的中，我们将接受和接种20名AFP+ HCC患者的多抗原DC疫苗。 A.4具体目的4。疫苗反应的免疫学评估。在此目标中，我们将表征对疫苗呈现抗原的免疫反应。确定NK响应；测试血清肿瘤标记物，生物标志物和Treg，并测试与免疫和临床反应的相关性。基于这些新信息的疫苗的合理设计应允许新疫苗实现免疫激活的更合理设计。公共卫生相关性：在全球范围内，每年至少有600,000例新的肝细胞癌病例，在美国有超过21,000例新病例，每年在美国肝细胞癌（HCC）死亡超过18,000例。在过去的几十年中（由于HCV感染的增加），HCC的发病率增加了，而5年生存率仅为2-8％。大多数疗法仅由于缺乏早期检测而进行姑息治疗。因此，HCC的发病率不断上升，并将成为未来半个世纪的更大健康问题。