DNA Vaccination Against Melanoma

黑色素瘤 DNA 疫苗

基本信息

批准号：
7728789
负责人：
ALAN N. HOUGHTON
金额：
$ 15.66万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7728789
关键词：
Active Immunization Address Agonist Amino Acid Sequence Antibodies Antibody Therapy Antigen Presentation Pathway Antigens Antitumor Response Autoantigens Autoimmune Diseases Autologous Binding Cancer Patient Cancer Vaccines Canis familiaris Carbohydrates Cells Clinical Research Clinical Trials Cyclophosphamide DNA DNA Vaccines Differentiation Antigens Dose Epitopes Family Goals Grant HLA A*0201 antigen Heterophile Antigens Homeostasis Human Immune Immune Tolerance Immune response Immune system Immunity Immunization Individual Laboratories Lead Link MHC Class I Genes Malignant Neoplasms Modeling Monophenol Monooxygenase Mus Normal Cell Passive Immunization Patients Peptides Phase I Clinical Trials Population Protein Family Proteins Recovery Safety Site Solid Neoplasm Specificity T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues Transgenes Tumor Antigens Vaccination Vaccine Design Vaccines Work cancer cell design glycosylation immunogenicity immunoregulation melanocyte melanoma mouse model mutant polypeptide response trafficking tumor

项目摘要

PROVIDED. Self antigens are recognized on cancers by the immune system of patients with cancer. Immune responses to self antigens can lead to rejection of cancer in laboratory models. Immunization against these antigens presents problems, however, because these are weak antigens. This proposal addresses limitations of the present molecularly defined cancer vaccines targeting self-antigens: 1) insufficient potency, 2) specificity for only individual epitopes or determinants, and 3) a need to modulate the immune system to favor response to vaccination. Using prototypical differentiation antigens of the tyrosinase family for models, creation of multiple heteroclitic epitopes and manipulation of protein stability and trafficking will be studied to increase potency of active immunization against cancer self-antigens. In the first Aim, DNA vaccines are designed to introduce multiple heteroclitic epitopes and to enhance antigen processing and presentation, followed by testing in laboratory treatment models for induction of antibody and T-cell responses and for antitumor activity. The second Aim investigates strategies to increase immune responses to vaccination through modulation of homeostatic immune cell recovery. Another strategy is explored to immunological target both cancer self-antigens and tumor stroma through active immunization or combination of active and passive immunization. The third Aim investigates immune modulation in combination with DNA vaccination in a clinical study. Finally, the last Aim explores DNA vaccination against cancer self-antigens in combination with vaccination against tumor stroma in a clinical study.

假如。癌症患者的免疫系统识别癌症上的自身抗原。免疫反应自身抗原可能导致实验室模型中癌症的排斥。针对这些抗原的免疫然而，存在问题，因为这些是弱抗原。该提案解决了以下限制：目前针对自身抗原的分子定义癌症疫苗：1）效力不足，2）特异性仅单个表位或决定簇，以及 3) 需要调节免疫系统以有利于对疫苗接种。使用酪氨酸酶家族的原型分化抗原作为模型，创建将研究多个异位表位以及蛋白质稳定性和运输的操纵，以增加针对癌症自身抗原的主动免疫的效力。在第一个目标中，DNA 疫苗旨在引入多个异位表位并增强抗原加工和呈递，然后在实验室治疗模型中测试诱导抗体和 T 细胞反应以及抗肿瘤活动。第二个目标是研究通过以下方式增强对疫苗接种的免疫反应的策略：调节稳态免疫细胞恢复。探索了另一种策略来免疫学靶向两者通过主动免疫或主动与被动结合，产生癌症自身抗原和肿瘤基质免疫接种。第三个目标是研究免疫调节与 DNA 疫苗接种的结合。临床研究。最后，最后一个目标是探索针对癌症自身抗原的组合DNA疫苗接种在临床研究中接种针对肿瘤基质的疫苗。