Melanoma vaccines using MHC-associated peptides

使用 MHC 相关肽的黑色素瘤疫苗

• 批准号: 7913480
• 负责人: Craig Lee Slingluff
• 金额: $ 7.54万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913480
• 关键词: Adjuvant; Agonist; Antigens; Area; Autoimmune Process; B-Lymphocytes; Binding Sites; Biology; CCL19 gene; CCL21 gene; CD4 Positive T Lymphocytes; CD8B1 gene; CXCL12 gene; CXCL13 gene; Cancer Vaccines; Cells; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Cutaneous; Dendritic Cells; Dermis; Emulsions; Event; Granulocyte-Macrophage Colony-Stimulating Factor; High Endothelial Venule; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunobiology; Inflammation; Inflammatory; Injection of therapeutic agent; Integrins; Langerhans cell; Lead; Location; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Melanoma Vaccine; Molecular; Myeloid Cells; Organ; Patients; Peptides; Peripheral; Prevalence; Process; Production; Proliferating; Signal Transduction; Site; Skin; Stimulus; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Toxic effect; Vaccination; Vaccines; Work; chemokine; chemokine receptor; improved; incomplete Freund' s adjuvant; lymph nodes; lymphotoxin beta; melanoma; novel; public health relevance; response; Adjuvant; Agonist; Antigens; Area; Autoimmune Process; B-Lymphocytes; Binding Sites; Biology; CCL19 gene; CCL21 gene; CD4 Positive T Lymphocytes; CD8B1 gene; CXCL12 gene; CXCL13 gene; Cancer Vaccines; Cells; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Communicable Diseases; Cutaneous; Dendritic Cells; Dermis; Emulsions; Event; Granulocyte-Macrophage Colony-Stimulating Factor; High Endothelial Venule; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunobiology; Inflammation; Inflammatory; Injection of therapeutic agent; Integrins; Langerhans cell; Lead; Location; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Melanoma Vaccine; Molecular; Myeloid Cells; Organ; Patients; Peptides; Peripheral; Prevalence; Process; Production; Proliferating; Signal Transduction; Site; Skin; Stimulus; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Toxic effect; Vaccination; Vaccines; Work; chemokine; chemokine receptor; improved; incomplete Freund' s adjuvant; lymph nodes; lymphotoxin beta; melanoma; novel; public health relevance; response

DESCRIPTION (provided by applicant): 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. We hypothesize that: (i) repeat vaccination with melanoma peptides and adjuvant may cause persistence of LNLA and creation of tertiary lymphoid organs at vaccine sites, (ii) extending immunization may result in a secondary set of immune regulatory influences, which could be blocked in a targeted manner if their prevalence and timing is defined, and (iii) antigen specific CD4+ and CD8+ T cells are induced locally at vaccine sites and may be generated by direct introduction of peptide antigens into a pre-induced immunization microenvironment. Thus, for the current proposal, we propose to perform 2 clinical trials combining immunization with a well- characterized multipeptide vaccine with extensive studies of tissue obtained from a replicate immunization site. Specific aims are: Aim 1. To determine whether repeat immunization (1-3 times) with "Adjuvant" with or without peptides induces lymph-node like aggregates (LNLA) and tertiary lymphoid organs (TLO) in skin, Aim 2. To determine whether extended immunization (4-6 vaccines) is associated with induction of immune regulatory processes in the vaccination site microenvironment /tertiary lymphoid organs, Aim 3. To characterize antigen-reactive CD4 and CD8 T cells in sites of immunization with a multipeptide vaccine. 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. PUBLIC HEALTH RELEVANCE: 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 present proposal is to characterize cellular and molecular events associated with induction of immune responses by melanoma vaccines, with the intent of improving the therapeutic potential of vaccines through a better understanding of these events.

描述（由申请人提供）：了解皮肤疫苗接种的免疫生物学的经典范式是，用佐剂提供的抗原会产生炎症刺激，这反过来又会诱导表皮Langerhans细胞成熟并迁移到淋巴结淋巴结。然而，辅助剂中用黑色素瘤重复疫苗接种与剧烈的慢性局部炎症有关，并且可能具有不同的生物学。自身免疫性和传染病的慢性炎症会导致不是经典淋巴区域的新淋巴组织。该过程称为“淋巴样新生成”，可能导致淋巴结淋巴结的三级淋巴器官（TLO）。我们已经观察到单次注射不完整的Freund的辅助和GM-CSF的乳液后，人类皮肤真皮中的淋巴结样聚集体（LNLA）。这些LNLA包含成熟的CD83+ DC-LAMP+树突状细胞，T细胞，B细胞和外周节结节地址（PNAD），表达了微血管，暗示了高内皮静脉。在重复的肽疫苗接种部位的初步研究表明，淋巴机新发生的其他特征，但也有骨料中调节细胞的证据。我们假设：：（i）用肽和辅助物重复接种疫苗可能会导致LNLA的持久性和在疫苗部位的第三级淋巴机构的持久性，（ii）免疫接种，延伸的免疫接种可能会导致次要的免疫调节性影响，如果其预期的和timii，则可以在特定的情况下（以及con）定义（并定义）（并定制）（并定义）（并定义）（并定义）（并定制），并且会导致（并定制），并且（并定义）（并定义），并且会导致（并定义）。 T细胞是在疫苗部位局部诱导的，可以通过将肽抗原直接引入预诱导的免疫微环境中产生。因此，对于当前的建议，我们建议进行2项临床试验，将免疫与良好特征的多肽疫苗与从复制免疫部位获得的组织进行广泛研究。具体目的是：目的1。确定具有或没有肽的“佐剂”重复免疫（1-3次）是否会诱导淋巴结（如骨料）（LNLA）（LNLA）和第三级淋巴机器人（TLO）（TLO）在皮肤中的目标2。淋巴器官，目的3。以多肽疫苗的免疫部位表征抗原反应性CD4和CD8 T细胞。这项工作的结果可能会改变我们对免疫生物学微环境中免疫生物学的理解，并确定联合疗法改善抗肿瘤免疫力的方法。 公共卫生相关性：癌症疫苗作为一种低毒性治疗的希望，可能利用免疫系统对癌症的反应，尤其是对黑色素瘤的反应。黑色素瘤疫苗可以在许多或大多数患者中诱导免疫反应，但临床影响令人失望。目前的建议是表征与黑色素瘤疫苗诱导免疫反应相关的细胞和分子事件，以通过更好地理解这些事件来改善疫苗的治疗潜力。