A MULTIPEPTIDE VACCINE IN MELANOMA PATIENTS WITH EVALUATION OF INJECTION SITE

黑色素瘤患者的多肽疫苗并评估注射部位

• 批准号: 8167189
• 负责人: Craig Lee Slingluff
• 金额: $ 16.44万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167189
• 关键词: Adjuvant; Antigens; Area; Autoimmune Process; B-Lymphocytes; Biology; Cancer Vaccines; Cells; Chronic; Clinical; Combined Modality Therapy; Communicable Diseases; Computer Retrieval of Information on Scientific Projects Database; Cutaneous; Dendritic Cells; Dermis; Emulsions; Evaluation; Event; Funding; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; High Endothelial Venule; Human; Immune response; Immune system; Immunity; Immunization; Immunobiology; Inflammation; Inflammatory; Injection of therapeutic agent; Institution; Langerhans cell; Lead; Location; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Mediating; Melanoma Vaccine; Molecular; Organ; Patients; Peptides; Peripheral; Process; Research; Research Personnel; Resources; Site; Skin; Source; Stimulus; T-Lymphocyte; Tissues; Toxic effect; United States National Institutes of Health; Vaccination; Vaccines; Work; improved; incomplete Freund' s adjuvant; lymph nodes; melanoma; response; vaccine efficacy

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 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反应，但临床效果却令人失望。 了解皮肤疫苗接种免疫生物学的经典范例是，用佐剂递送的抗原会产生炎症刺激，进而诱导表皮朗格汉斯细胞成熟并迁移到引流淋巴结。 然而，用佐剂中的黑色素瘤肽重复接种与严重的慢性局部炎症有关，并且可能具有不同的生物学特性。 自身免疫性疾病和传染病中的慢性炎症可能会在非经典淋巴区域的位置产生新的淋巴组织。 这个过程被称为“淋巴新生”，可以产生功能类似于淋巴结的第三淋巴器官（TLO）。 我们在单次注射不完全弗氏佐剂加 GM-CSF 的乳液后，在人体皮肤真皮中观察到淋巴结样聚集体 (LNLA)。 这些 LNLA 含有成熟的 CD83+DC-LAMP+ 树突状细胞、T 细胞、B 细胞和表达外周节点地址素 (PNAd) 的微血管，提示高内皮微静脉。 对重复佐剂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。 对于当前的提案，我们建议通过将免疫与充分表征的多肽疫苗结合起来，并对从重复免疫位点获得的组织进行广泛研究，来定义黑色素瘤人类免疫微环境中的细胞和分子事件。 总体假设是，这些疫苗位点的免疫反应是通过淋巴新生和 TLO 介导的，随着这些过程和相关监管过程的阐明，我们预计能够找到提高疫苗功效的机会。 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，并确定提高抗肿瘤免疫力的联合疗法的方法。