Antibodies to melanoma vaccine peptides

癌症疫苗已经有效地诱导了黑色素瘤和其他疾病患者的T细胞反应 癌症，但临床影响有限。大多数癌症疫苗都被设计成诱导CD8+T细胞 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 在抗癌免疫中起着关键作用。我们发现，一种旨在刺激CD4+T细胞的疫苗可以诱导 大多数黑色素瘤患者的Th1占优势的CD4+辅助T细胞。此外，这种疫苗由一种 混合了6个中间长度(14-23个氨基酸)的黑色素瘤辅助多肽(6MHP)，已有临床应用 活动度高，在一些患者中持久存在，与CD4+辅助性T细胞有显著相关性 在两个不同的临床试验中的反应和患者存活率。直到最近，这些疫苗的重点一直是 T细胞反应。然而，我们最近研究了多肽和抗体的诱导。 发现高滴度循环免疫球蛋白反应与显著改善患者存活率有关。The Ab. 应答也与辅助性T细胞应答有关，但最好的临床结果是那些患有 抗体和T细胞都有反应。黑色素瘤多肽疫苗诱导的抗体是否参与尚不清楚 或仅仅是免疫激活的生物标志物。目前也不清楚在多大程度上存在差异 疫苗佐剂可增强或抑制这些抗体反应。与以下因素相关的良好临床结果 抗体反应，特别是抗体和T细胞反应的结合，支持这样一个广泛的假设 抗体应答可能有助于6 MHP疫苗的临床应用。自从多肽疫苗的临床试验以来 在很大程度上忽略了多肽疫苗抗体反应的存在和功能意义，它既是 对确定多肽诱导抗体的免疫学和抗癌作用具有重要意义和新颖性。我们 假设抗6MHP的抗体与抗原结合并产生大的免疫复合物(IC)，从而促进递送到 抗原提呈细胞(APC)和支持树突状细胞(DC)和B细胞的内化和交叉提呈 细胞通过FcγR和补体受体2(CR2)，从而增强抗原递呈和抗肿瘤 活动。我们还假设Toll样受体(TLR)激动剂可能增加对6MHP的抗体反应 疫苗，并可能调节同型，免疫球蛋白亚型，并诱导记忆B细胞。具体目标是： 目的1.评价疫苗佐剂对黑色素瘤疫苗中多肽抗体应答的影响 诱导记忆B细胞；目的2.确定形成多肽的免疫复合体(IC)的性质 疫苗以及它们是否促进FCR介导的APC的摄取和呈递。

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.