Antibodies to melanoma vaccine peptides

黑色素瘤疫苗肽抗体

• 批准号: 9378813
• 负责人: Craig Lee Slingluff
• 金额: $ 8.05万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378813
• 关键词: Adjuvant; Agonist; Amino Acids; Antibodies; Antibody Response; Antigen Presentation; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Biological; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Control; Cancer Vaccines; Clinical; Clinical Trials; Complement 3d Receptors; Cross Presentation; Cyclophosphamide; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Epitopes; Favorable Clinical Outcome; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin G; Immunologic Markers; Immunologics; Immunotherapy; Length; Malignant Neoplasms; Mediating; Melanoma Vaccine; Memory B-Lymphocyte; Nature; Outcome; Patients; Peptide Vaccines; Peptides; Reporting; Role; Serum; T cell response; Toll-like receptors; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccines; antigen binding; cancer clinical trial; design; immune activation; immune checkpoint blockade; improved; in vivo; inhibiting antibody; melanoma; novel; patient population; response; uptake; Adjuvant; Agonist; Amino Acids; Antibodies; Antibody Response; Antigen Presentation; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Biological; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Control; Cancer Vaccines; Clinical; Clinical Trials; Complement 3d Receptors; Cross Presentation; Cyclophosphamide; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Epitopes; Favorable Clinical Outcome; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin G; Immunologic Markers; Immunologics; Immunotherapy; Length; Malignant Neoplasms; Mediating; Melanoma Vaccine; Memory B-Lymphocyte; Nature; Outcome; Patients; Peptide Vaccines; Peptides; Reporting; Role; Serum; T cell response; Toll-like receptors; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccines; antigen binding; cancer clinical trial; design; immune activation; immune checkpoint blockade; improved; in vivo; inhibiting antibody; melanoma; novel; patient population; response; uptake

Cancer vaccines have been effective for inducing T cell responses in patients with melanoma and other cancers, but clinical impact has been limited. Most cancer vaccines have been designed to induce CD8+ T cell responses to cancer antigens, but a growing body of data demonstrates that CD4+ “helper” T cells have pivotal roles in anticancer immunity. We have found that a vaccine designed to stimulate CD4+ T cells induces Th1-dominant CD4+ helper T cells in most melanoma patients. In addition, this vaccine, comprised of a mixture of 6 intermediate length (14-23 amino acids) melanoma “helper” peptides (6MHP), have had clinical activity, durable in some patients, and there has been significant correlation between CD4+ helper T cell response and patient survival in two separate clinical trials. Until recently, the focus of these vaccines has been on T cell responses. However, we have recently examined the induction of antibody (Ab) to the peptides and found high titer circulating IgG responses that are associated with significantly better patient survival. The Ab response also was associated with a helper T cell response, but the best clinical outcome was for those with both Ab and T cell responses. It is not known whether Ab induced by melanoma peptide vaccines participates in antitumor activity or is just a biomarker of immune activation. It also is not clear to what extent various vaccine adjuvants may augment or inhibit these Ab responses. The favorable clinical outcome associated with the Ab responses, and especially the combination of Ab and T cell responses, favors the broad hypothesis that the Ab responses may contribute to clinical benefit of 6MHP vaccines. Since clinical trials of peptide vaccines have largely ignored the presence and functional significance of Ab responses to peptide vaccines, it is both significant and novel to determine the immunologic and anti-cancer effects of peptide-induced antibodies. We hypothesize that Abs to 6MHP bind antigen and create large immune complexes (ICs) that facilitate delivery to antigen-presenting cells (APC) and support internalization and cross-presentation by dendritic cells (DC) and B cells via the FcγR and complement receptor 2 (CR2), thus augmenting antigen presentation and antitumor activity. We also hypothesize that toll-like receptor (TLR) agonists may increase Ab responses to 6MHP vaccines and may modulate the isotype, IgG subtypes, and induction of memory B cells. Specific aims are: Aim 1. To assess the impact of vaccine adjuvants on Ab response to peptides in melanoma vaccines and on induction of memory B cells; Aim 2. To determine the nature of immune complexes (ICs) formed to peptides in the vaccines and whether they facilitate FcR-mediated uptake and presentation by APC.

癌症疫苗对黑色素瘤和其他患者的T细胞反应有效 癌症，但临床影响受到限制。大多数癌症疫苗的设计用于诱导CD8+ T 细胞对癌症抗原的反应，但是越来越多的数据表明CD4+“助手” T细胞具有 抗癌免疫中关键作用。我们发现旨在刺激CD4+ T细胞的疫苗会诱导 大多数黑色素瘤患者中Th1-主导的CD4+辅助T细胞。此外，该疫苗包括 6个中间长度（14-23个氨基酸）黑色素瘤“助手”肽（6MHP）的混合物具有临床 活性，某些患者耐用，CD4+辅助T细胞之间存在显着相关性 在两个单独的临床试验中的反应和患者生存。直到最近，这些疫苗的重点一直是 在T细胞反应上。但是，我们最近研究了肽的抗体（AB）和 发现高滴度循环的IgG反应与患者生存更加明显相关。 AB 反应也与辅助T细胞反应有关，但最好的临床结果是 AB和T细胞反应。尚不知道黑色素瘤诱发的AB是否参与 在抗肿瘤活性中，只是免疫激活的生物标志物。尚不清楚各种程度 疫苗调节器可能会增加或抑制这些AB反应。与 AB反应，尤其是AB和T细胞反应的组合，有利于广泛的假设，即 AB反应可能会导致6MHP疫苗的临床益处。由于胡椒疫苗的临床试验 在很大程度上忽略了AB对胡椒疫苗反应的存在和功能意义，这两者都是 重要而新颖的，以确定胡椒诱导抗体的免疫和抗癌作用。我们 假设ABS与6MHP结合抗原并产生大型免疫复合物（IC），以促进递送到 抗原呈递细胞（APC）并支持树突状细胞（DC）和B的内在化和交叉表达 通过FcγR和补体受体2（CR2）的细胞，从而增加了抗原表现和抗毒液 活动。我们还假设Toll样受体（TLR）激动剂可能会增加对6MHP的AB反应 疫苗并可能调节记忆B细胞的同种型，IgG亚型和诱导。具体目的是： 目标1。评估疫苗调节器对黑色素瘤疫苗中对辣椒的反应的影响 诱导记忆B细胞；目标2。确定形成肽的免疫复合物（IC）的性质 疫苗以及它们是否促进了FCR介导的摄取和APC的摄取。