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

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）：理解皮肤接种免疫生物学的经典范例是，与佐剂一起递送的抗原产生炎症刺激，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。我们假设：（i）用黑色素瘤肽和佐剂重复接种可能导致LNLA的持续存在和在疫苗部位产生三级淋巴样器官，（ii）延长免疫可能导致第二组免疫调节影响，如果确定了它们的流行和时机，则可以以靶向方式阻断它们，和（iii）抗原特异性CD 4+和CD 8 + T细胞在疫苗位点被局部诱导，并且可以通过将肽抗原直接引入预诱导的免疫微环境中而产生。因此，对于当前提案，我们建议进行2项临床试验，将免疫与充分表征的多肽疫苗结合，并对从重复免疫部位获得的组织进行广泛研究。具体目标是：目标1。为了确定用具有或不具有肽的“佐剂”重复免疫（1-3次）是否在皮肤中诱导淋巴结样聚集体（LNLA）和三级淋巴器官（TLO），目的2。确定扩大免疫（4-6种疫苗）是否与疫苗接种部位微环境/三级淋巴器官中免疫调节过程的诱导相关，目的3。表征用多肽疫苗免疫的部位中的抗原反应性CD 4和CD 8 T细胞。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。 公共卫生相关性：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的反应，特别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应答，但临床效果令人失望。目前的建议是表征与黑色素瘤疫苗诱导免疫应答相关的细胞和分子事件，目的是通过更好地理解这些事件来提高疫苗的治疗潜力。