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.

癌症疫苗已经有效地诱导患有黑素瘤和其他癌症的患者的T细胞应答。 癌症，但临床影响有限。大多数癌症疫苗被设计为诱导CD 8 + T细胞 细胞对癌抗原的反应，但越来越多的数据表明，CD 4+“辅助”T细胞具有 在抗癌免疫中的关键作用。我们已经发现，设计用于刺激CD 4 + T细胞的疫苗诱导 大多数黑色素瘤患者的Th 1-显性CD 4+辅助性T细胞此外，这种疫苗由一种 6个中等长度（14-23个氨基酸）的黑素瘤“辅助”肽（6 MHP）的混合物，已经具有临床应用前景。 活动，持久的一些患者，并已显着相关性CD 4+辅助性T细胞 两项独立临床试验中的反应和患者生存率。直到最近，这些疫苗的重点一直是 T细胞反应。然而，我们最近已经检查了针对肽的抗体（Ab）的诱导， 发现高滴度循环IgG应答与显著更好的患者存活率相关。所述Ab 应答也与辅助性T细胞应答相关，但最佳临床结果是那些 抗体和T细胞反应。目前尚不清楚黑色素瘤肽疫苗诱导的Ab是否参与 或者仅仅是免疫激活的生物标志物。目前还不清楚在多大程度上， 疫苗佐剂可增强或抑制这些Ab应答。有利的临床结局与 抗体应答，特别是抗体和T细胞应答的组合，支持广泛的假设， 抗体应答可能有助于6 MHP疫苗的临床获益。自从肽疫苗的临床试验 在很大程度上忽略了抗体对肽疫苗的反应的存在和功能意义， 这对于确定肽诱导的抗体的免疫学和抗癌作用是有意义的和新颖的。我们 假设抗6 MHP抗体结合抗原并产生大的免疫复合物（IC）， 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）介导细胞，从而增强抗原呈递和抗肿瘤作用。 活动我们还假设Toll样受体（TLR）激动剂可能会增加抗体对6 MHP的反应， 并且可以调节同种型、IgG亚型和记忆B细胞的诱导。具体目标是： 目标1。为了评估疫苗佐剂对黑素瘤疫苗中肽的Ab应答的影响， 记忆B细胞的诱导;目的2.为了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FcR介导的APC摄取和呈递。