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

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.

癌症疫苗可有效诱导黑色素瘤和其他疾病患者的 T 细胞反应 癌症，但大多数癌症疫苗的设计目的是诱导 CD8+ T。 细胞对癌症抗原的反应，但越来越多的数据表明 CD4+“辅助”T 细胞 我们发现，旨在刺激 CD4+ T 细胞的疫苗可诱导抗癌免疫。 大多数黑色素瘤患者中以 Th1 为主的 CD4+ 辅助 T 细胞此外，该疫苗还包含 6 种中等长度（14-23 个氨基酸）黑色素瘤“辅助”肽 (6MHP) 的混合物，已在临床上获得应用 活性，在某些患者中持久，并且 CD4+ 辅助 T 细胞之间存在显着相关性 直到最近，这些疫苗的焦点一直是两个独立临床试验的反应和患者存活率。 然而，我们最近研究了肽和抗体 (Ab) 的诱导。 发现高滴度的循环 IgG 反应与显着提高患者生存率相关。 反应也与辅助 T 细胞反应相关，但最好的临床结果是那些患有 目前尚不清楚黑色素瘤肽疫苗诱导的 Ab 是否参与。 抗肿瘤活性或只是免疫激活的生物标志物，目前还不清楚其差异程度如何。 疫苗佐剂可能会增强或抑制这些抗体反应，从而带来良好的临床结果。 Ab 反应，尤其是 Ab 和 T 细胞反应的组合，支持这样一个广泛的假设： 自肽疫苗临床试验以来，抗体反应可能有助于 6MHP 疫苗的临床获益。 在很大程度上忽略了抗体对肽疫苗反应的存在和功能意义，它既是 对于确定肽诱导抗体的免疫学和抗癌作用具有重要且新颖的意义。 培养出 6MHP 抗体结合抗原并产生大型免疫复合物 (IC)，从而促进递送至 抗原呈递细胞 (APC) 并支持树突状细胞 (DC) 和 B 的内化和交叉呈递 通过 FcγR 和补体受体 2 (CR2) 作用于细胞，从而增强抗原呈递和抗肿瘤 我们还发现 Toll 样受体 (TLR) 激动剂可能会增加对 6MHP 的抗体反应。 疫苗并可能调节同种型、IgG 亚型和记忆 B 细胞的诱导。 目标 1. 评估疫苗佐剂对黑色素瘤疫苗中肽的抗体反应的影响以及 诱导记忆 B 细胞；目标 2. 确定与肽形成的免疫复合物 (IC) 的性质 疫苗以及它们是否促进 APC 介导的 FcR 摄取和呈递。