MULTI-EPITOPE MELANOMA VACCINES FOR CD4 AND CD8 T-CELLS

针对 CD4 和 CD8 T 细胞的多表位黑色素瘤疫苗

• 批准号: 7413687
• 负责人: Craig Lee Slingluff
• 金额: $ 38.72万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-06 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413687
• 关键词: 12 Melanoma Peptide Vaccine; 6 Helper Peptide; Adjuvant; Alanine; Aliquot; Alleles; Antigen Targeting; Antigens; Applications Grants; Area; Biological Assay; Biopsy; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CSF2 gene; CTAG1 gene; Cancer Therapy Evaluation Program; Cells; Certification; Cessation of life; Class; Clinical; Clinical Trials; Consent; Cryopreservation; Cyclization; Data; Dendritic cell activation; Disease regression; Eastern Cooperative Oncology Group; End Point; Enrollment; Epitopes; Frequencies; Funding; Glutamine; Granulocyte-Macrophage Colony-Stimulating Factor; Group Practice; HLA-A1 Antigen; HLA-A2 Antigen; HLA-A31; HLA-DR Antigens; Harvest; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Human; Immune response; Immunologic Memory; Immunologic Monitoring; Immunologics; Immunotherapy; Independent Scientist Award; Institution; Laboratories; Limb structure; Lymphoid; MAGE-A10 antigen; MART-1 Tumor Antigen; MHC Class I Genes; MHC Class II Genes; Measurable; Melan-A protein; Melanoma Cell; Melanoma Vaccine; Memory; Monophenol Monooxygenase; Montanide ISA-51; Multicenter Studies; N-terminal; Numbers; Outcome; Patients; Peptide Synthesis; Peptide Vaccines; Peptides; Phase II Clinical Trials; Phenotype; Process; Proteins; Randomized; Reporting; Secondary Immunization; Sentinel; Shipping; Ships; Site; Staging; T-Lymphocyte; TNFRSF10A gene; Testing; Tetanus; Tetanus Helper Peptide; Tissue Sample; Tissues; Universities; University of Pittsburgh Cancer Institute; Upper arm; Vaccination; Vaccine Adjuvant; Vaccines; Virginia; Week; Work; booster vaccine; cost; cytokine; day; experience; gp100(17-25) peptide; immunogenic; immunogenicity; improved; melanoma; melanoma-associated antigen-A1; peripheral blood; prevent; protein aminoacid sequence; response; tumor

DESCRIPTION (provided by applicant): Peptide antigens recognized by human melanoma-reactive T cells can be incorporated in vaccines to induce immune responses against melanoma. Most work in this area has been limited to the use of single antigens, or few antigens, targeting only CD8+ T cells. These vaccines induce CD8+ T cell responses, but often of low magnitude, and objective tumor regressions have been uncommon. To improve vaccine strategies, it may help to increase the number of antigens targeted, to increase the magnitude of responses, to target both CD4 and CD8 T cells, and to increase persistence of the immune response through induction of memory. CD4 responses appear to be critical for immunologic memory, and for dendritic cell activation. Nonspecific stimulation of CD4 T cells may induce helper T cell responses at the site of vaccination; however, maintaining CD4 T-cell help at sites of tumor may require that they are stimulated more specifically toward melanoma antigens. Now that multiple peptide epitopes for helper T cells have been defined, it is feasible to assess their immunogenicity, and to determine whether they increase the magnitude and persistence of CD8 responses. The immunologic effects of vaccination with a multipeptide vaccine targeting CD4 and CD8 T cells will be evaluated in the clinical trial E1602. The peptide antigens used in this trial include (i) a cocktail of 12 melanoma peptides restricted by Class I MHC molecules HLA-A1, A2, or A3 (12MP), (ii) a cocktail of 6 melanoma helper peptides restricted by HLA-DR molecules (6MHP), and (iii) a modified tetanus peptide, restricted by HLA-DR molecules (tet). Patients with advanced melanoma will be randomized to one of 4 vaccine strategies: (a) 12MP only, (b) 12MP + tet, (c) 12MP + 6 MHP, and (d) 6MHP only. The current application is for immunologic studies of T cell responses to these multipeptide vaccines, as well as for shipping costs and for costs of vaccine adjuvant. Blood and tissues for immune monitoring will be shipped, prepared, and cryopreserved centrally at the Immune Monitoring and Cellular Products Laboratory (IMCPL) at the University of Pittsburgh, which is the Core Laboratory for the Eastern Cooperative Oncology Group (ECOG) and has experience and certification in cryopreservation. The cellular immune monitoring assays will be performed by the Human Immune Therapy Center Laboratory at the University of Virginia. Cytokine assays will be done at the Pittsburgh IMCPL. Specific aims are: 1) To estimate whether addition of helper peptides to a vaccine containing multiple Class I MHC-restricted peptides augments T-cell responses to the Class I restricted peptides; 2) To characterize the phenotype of vaccine-induced CD8+ T cells for effector and memory phenotypes; 3) To determine the helper T cell response to tetanus peptide and to each of 6 melanoma helper peptides, restricted by multiple HLA-DR molecules; 4} To obtain preliminary data on whether booster vaccination every three months may maintain immune responses to a peptide vaccine, in patients with stage IV melanoma; and 5) To obtain preliminary data on whether cellular immune responses to a 12-peptide vaccine may correlate with clinical outcome, among the four arms of this study.

说明书(申请人提供)：由人类黑色素瘤反应性T细胞识别的多肽抗原可被加入疫苗中，以诱导对黑色素瘤的免疫反应。在这一领域的大多数工作仅限于使用单一抗原或少数抗原，仅针对CD8+T细胞。这些疫苗诱导CD8+T细胞反应，但通常幅度较小，客观上的肿瘤消退并不常见。为了改进疫苗策略，它可能有助于增加靶向抗原的数量，增加反应的幅度，同时针对CD4和CD8T细胞，并通过诱导记忆来增加免疫反应的持久性。CD4反应似乎对免疫记忆和树突状细胞的激活至关重要。对CD4T细胞的非特异性刺激可以在接种部位诱导辅助T细胞反应；然而，要维持肿瘤部位的CD4T细胞帮助，可能需要对黑色素瘤抗原更具特异性地刺激它们。现在已经定义了辅助T细胞的多个多肽表位，可以评估它们的免疫原性，并确定它们是否增加了CD8反应的大小和持久性。针对CD4和CD8T细胞的多肽疫苗接种的免疫学效果将在临床试验E1602中进行评估。本试验中使用的多肽抗原包括(I)受第I类MHC分子HLA-A1、A2或A3限制的12个黑色素瘤多肽的鸡尾酒(12MP)，(Ii)由人类白细胞抗原DR分子限制的6个黑色素瘤辅助肽的鸡尾酒(6MHP)，以及(Iii)由人类白细胞抗原DR分子限制的改良破伤风多肽(TET)。晚期黑色素瘤患者将被随机分成4种疫苗策略之一：(A)仅12MP，(B)12MP+TET，(C)12MP+6MHP，以及(D)仅6MHP。目前的应用是T细胞对这些多肽疫苗反应的免疫学研究，以及运输成本和疫苗佐剂的成本。用于免疫监测的血液和组织将在匹兹堡大学的免疫监测和细胞产品实验室(IMCPL)集中运输、准备和冷冻保存，该实验室是东方合作肿瘤组(ECOG)的核心实验室，在冷冻保存方面具有经验和认证。细胞免疫监测分析将由弗吉尼亚大学人类免疫治疗中心实验室进行。细胞因子分析将在匹兹堡IMCPL进行。具体目标是：1)估计在含有多个I类MHC限制性多肽的疫苗中加入辅助肽是否能增强T细胞对I类限制性多肽的反应；2)鉴定疫苗诱导的CD8+T细胞的效应和记忆表型的表型；3)确定辅助性T细胞对破伤风多肽和受多个HLA-DR分子限制的6个黑色素瘤辅助肽的反应；4)获得关于在IV期黑色素瘤患者中每三个月加强接种一次多肽疫苗是否可以维持对多肽疫苗的免疫反应的初步数据；5)在这项研究的四个分支中，获得对12肽疫苗的细胞免疫反应是否与临床结果相关的初步数据。