Dendritic Cell Biology and Therapy

树突状细胞生物学和治疗

• 批准号: 8513810
• 负责人: Olivera J Finn
• 金额: $ 37.53万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8513810
• 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

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.

本项目是先前项目1和项目2研究的延续。我们获得了证据