A MULTIPEPTIDE VACCINE IN MELANOMA PATIENTS WITH EVALUATION OF INJECTION SITE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 癌症疫苗有望成为一种低毒性治疗方法，可以利用免疫系统对癌症，特别是黑色素瘤的反应。 黑色素瘤疫苗可以在许多或大多数患者中诱导免疫应答，但临床效果令人失望。 用于理解皮肤接种的免疫生物学的经典范例是与佐剂一起递送的抗原产生炎性刺激，其进而诱导表皮朗格汉斯细胞成熟并迁移至引流淋巴结。 然而，用佐剂中的黑素瘤肽重复接种与显著的慢性局部炎症相关，并且可能具有不同的生物学。 自身免疫性和感染性疾病中的慢性炎症可导致在非典型淋巴区域的位置产生新的淋巴组织。 这一过程被称为“淋巴新生”，可产生功能类似淋巴结的三级淋巴器官（TLO）。 我们已经观察到淋巴结样聚集体（LNLA）在人皮肤真皮后，一个单一的注射不完全弗氏佐剂加GM-CSF的乳液。 这些LNLA含有成熟的CD 83 +DC-LAMP+树突细胞、T细胞、B细胞和外周淋巴结地址素（PNAd）表达微血管，提示高内皮微静脉。 用佐剂重复肽疫苗接种部位的初步研究显示了淋巴新生的其他特征，但也有证据表明聚集体中存在调节细胞。 对于目前的建议，我们建议定义的细胞和分子事件的免疫微环境中的人与黑色素瘤，通过结合免疫与一个良好的特点的多肽疫苗从一个重复免疫部位获得的组织的广泛研究。 总体假设是，这些疫苗位点的免疫应答是通过淋巴新生和TLO介导的，我们预计能够确定提高疫苗效力的机会，因为这些过程和相关的调控过程得到阐明。 这项工作的结果可能会改变我们对免疫微环境中免疫生物学的理解，并确定联合治疗以提高抗肿瘤免疫力的方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer vaccines hold promise as a low toxicity treatment that may harness the immune system's response to cancer and to melanoma in particular. Melanoma vaccines can induce immune responses in many or most patients, but the clinical impact has been disappointing. The classic paradigm for understanding the immunobiology of cutaneous vaccination is that antigen delivered with an adjuvant creates an inflammatory stimulus, which in turn induces epidermal Langerhans cells to mature and to migrate to draining lymph nodes. However, repeat vaccination with melanoma peptides in adjuvant is associated with dramatic chronic local inflammation and may have different biology. Chronic inflammation in autoimmune and infectious diseases can lead to new lymphoid tissues in locations that are not classic lymphoid areas. This process, termed "lymphoid neogenesis," can result in tertiary lymphoid organs (TLO) that function like lymph nodes. We have observed lymph node-like aggregates (LNLA) in the dermis of human skin after a single injection of an emulsion of incomplete Freund's adjuvant plus GM-CSF. These LNLA contain mature CD83+DC-LAMP+ dendritic cells, T cells, B cells, and peripheral node addressin (PNAd) expressing microvessels suggestive of high endothelial venules. Preliminary studies in sites of repeated peptide vaccination with adjuvant show other features of lymphoid neogenesis, but there also is evidence of regulatory cells in the aggregates. For the current proposal, we propose to define the cellular and molecular events in the immunization microenvironment in humans with melanoma, by combining immunization with a well-characterized multipeptide vaccine with extensive studies of tissue obtained from a replicate immunization site. The overarching hypothesis is that the immune response at these vaccine sites is mediated through lymphoid neogenesis and TLOs, and we anticipate being able to identify opportunities for improving vaccine efficacy as these processes and associated regulatory processes are elucidated. The results of this work will likely change our understanding of the immunobiology in the immunization microenvironment and identify approaches for combination therapies to improve antitumor immunity.