Dendritic Cell Biology and Therapy

树突状细胞生物学和治疗

基本信息

批准号：
8704120
负责人：
Olivera J Finn
金额：
$ 38.59万
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：
2011
资助国家：
美国
起止时间：
2011-09-22 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704120
关键词：
Address Adjuvant Animal Model Antibodies Antibody Formation Antigen Targeting Antigens Autoimmunity Biological Markers Breast CD4 Positive T Lymphocytes Cancer Patient Cancer Vaccines Cell Therapy Cells Cellular biology Clinical Clinical Trials Colon Complex Data Dendritic Cells Diagnosis Disease Drug Formulations Frequencies Future Glycopeptides Goals Grant Helper-Inducer T-Lymphocyte Human Immune Immune response Immune system In Vitro Instruction Link Lung Macaca mulatta Malignant neoplasm of pancreas Memory Methods Modeling Monkeys Mucin-1 Staining Method Mus Pancreas Particulate Patients Peptide Vaccines Peptides Phase Phenotype Population Prevention Primates Process Resected Safety Suggestion T cell response T-Lymphocyte Tandem Repeat Sequences Testing Threonine Transgenic Mice Tumor Antigens Vaccinated Vaccines base cancer prevention clinical efficacy cytokine efficacy trial immune activation in vivo mouse model neoplastic cell next generation patient population pre-clinical research study response tumor vaccine candidate vaccine efficacy

项目摘要

This project is a continuation of studies performed in the previous Projects 1 and 2. We obtained evidence that helper T cell responses and antibody responses to the MUC1 tumor antigen peptide are reduced in MUCITg mice compared to WT mice but when the peptide carried 0-linked GalNac residues, representing hypoglycosylated tumor form of MUC1, MUCITg mice responded equally well as the WT mice. We hypothesize that the difference in responses to the MUC1 peptide versus glycopeptide presented by DC is due to tolerance because MUC1 peptide is perceived as "self," while tumor-specific glycopeptide represents abnormal self and thus is perceived as foreign. Similar state of tolerance may characterize MUC1 peptide specific T cells in patients and thus a related hypothesis is that MUC1 glycopeptide is a better vaccine candidate than the peptide that has been used to date. Our third hypothesis is that immune parameters (biomarkers) of efficacy exist as complex signatures of immune activation of DC and T cells and our goal is to identify those that can predict anti-tumor efficacy of MUC1 vaccines. We propose to test these hypotheses in human MUC1 transgenic mice and MUC1 peptide and glycopeptide specific TCR transgenic mice, as well as in rhesus macaques using rhesus MUC1 sequences. We propose the following specific aims: Specific Aim 1: We will determine what controls differences in immune responses to the self/tumor antigen MUC1 in MUCITg mice when MUC1 peptide (self?) versus MUC1 glycopeptide (foreign?) are used as antigens and targeted to adjuvant-activated DC. Specific Aim 2: We will test different MUC1 vaccines in rhesus macaques The proposed experiments will draw on observations already made or to tte made in the Projects 1 and 3 that identify important parameters of T cell and DC activation. The ultimate goal of Project 2 is to define the next generation of MUC1 vaccines.capable of eliciting an immune response with a predetermined signature of anti-tumor efficacy.

该项目是在先前项目1和2中进行的研究的延续。我们获得了证据在MUC1肿瘤抗原肽中，辅助T细胞反应和抗体反应减少了与WT小鼠相比，Mucitg小鼠相比，但是当肽携带0连接的GalNAC残基时，代表 MUC1的低糖基化肿瘤形式，Mucitg小鼠的反应与WT小鼠一样好。我们假设对DC提出的对MUC1肽与糖肽的反应差异为由于耐受性，因为MUC1肽被认为是“自我”，而肿瘤特异性糖肽代表异常的自我，因此被认为是外国人。类似的耐受状态可能是MUC1肽的特征患者的特定T细胞，因此相关的假设是MUC1糖肽是一种更好的疫苗候选人比迄今为止使用的肽。我们的第三个假设是免疫参数（生物标志物）作为DC和T细胞免疫激活的复杂特征而存在，我们的目标是确定可以预测MUC1疫苗抗肿瘤功效的人。我们建议检验这些假设在人MUC1转基因小鼠，MUC1肽和糖肽特异性TCR转基因小鼠中也如使用恒河猕猴中的猕猴序列。我们提出以下特定目标：具体 AIM 1：我们将确定哪些控制自我/肿瘤抗原MUC1的免疫反应差异 MUCITG小鼠MUC1肽（SEXS？）与MUC1糖肽（外源？）用作抗原和针对辅助激活的直流。特定目标2：我们将在恒河猕猴中测试不同的MUC1疫苗拟议的实验将借鉴已经进行的观察结果或项目1和3中的TTE 确定T细胞和直流激活的重要参数。项目2的最终目标是定义下一代MUC1疫苗。可引起具有预定签名的免疫反应抗肿瘤功效。