DNA Vaccination Against Melanoma

黑色素瘤 DNA 疫苗

• 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
• 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

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.

提供了 自身抗原被癌症患者的免疫系统识别。免疫应答 在实验室模型中，自身抗原可导致癌症排斥。针对这些抗原的免疫 然而，由于这些是弱抗原，因此存在问题。该提案解决了 目前靶向自身抗原的分子定义的癌症疫苗：1）效力不足，2）对 只有个别表位或决定簇，和3）需要调节免疫系统，以有利于响应 预防针使用酪氨酸酶家族的原型分化抗原作为模型， 将研究多个异型表位和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效力。在第一个目标中，DNA疫苗被设计成 引入多个异型表位并增强抗原加工和呈递，然后 在实验室治疗模型中检测抗体和T细胞应答的诱导以及抗肿瘤 活动第二个目的是研究通过以下方式增加对疫苗接种的免疫应答的策略： 调节稳态免疫细胞恢复。另一种策略是探索免疫目标， 通过主动免疫或主动与被动相结合， 次免疫第三个目的是研究免疫调节与DNA疫苗接种相结合， 临床研究最后，最后一个目的是探索针对癌症自身抗原的DNA疫苗接种， 在一项临床研究中接种抗肿瘤基质的疫苗。