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: 7260529
• 负责人: Craig Lee Slingluff
• 金额: $ 38.53万
• 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/7260529
• 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.

描述（由申请人提供）：可将人黑素瘤反应性T细胞识别的肽抗原掺入疫苗中，以诱导针对黑素瘤的免疫应答。该领域的大多数工作仅限于使用单一抗原或少数抗原，仅靶向CD 8 + T细胞。这些疫苗诱导CD 8 + T细胞应答，但通常幅度较低，客观肿瘤消退并不常见。为了改善疫苗策略，它可能有助于增加靶向抗原的数量，增加应答的幅度，靶向CD 4和CD 8 T细胞，并通过诱导记忆来增加免疫应答的持久性。CD 4应答似乎对免疫记忆和树突状细胞活化至关重要。CD 4 T细胞的非特异性刺激可能在疫苗接种部位诱导辅助性T细胞应答;然而，在肿瘤部位维持CD 4 T细胞的帮助可能需要它们更特异地刺激黑色素瘤抗原。既然已经确定了辅助性T细胞的多个肽表位，就可以评估它们的免疫原性，并确定它们是否增加了CD 8应答的幅度和持久性。将在临床试验E1602中评价靶向CD 4和CD 8 T细胞的多肽疫苗接种的免疫学效应。本试验中使用的肽抗原包括（i）受I类MHC分子HLA-A1、A2或A3限制的12种黑素瘤肽的混合物（12 MP），（ii）受HLA-DR分子限制的6种黑素瘤辅助肽的混合物（6 MHP），和（iii）受HLA-DR分子限制的修饰破伤风肽（泰特）。晚期黑色素瘤患者将随机接受4种疫苗策略之一：（a）仅12 MP，（B）12 MP+泰特，（c）12 MP + 6 MHP，（d）仅6 MHP。目前的应用是用于对这些多肽疫苗的T细胞应答的免疫学研究，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、制备和冷冻保存，IMCPL是东部肿瘤协作组（ECOG）的核心实验室，在冷冻保存方面具有经验和认证。细胞免疫监测试验将由弗吉尼亚大学人类免疫治疗中心实验室进行。将在Pittsburgh IMCPL进行细胞因子试验。具体目标是：1）评估向含有多个I类MHC限制性肽的疫苗中添加辅助肽是否增强T细胞对I类限制性肽的应答; 2）表征疫苗诱导的CD 8 + T细胞的效应和记忆表型的表型; 3）确定辅助T细胞对破伤风肽和6种黑素瘤辅助肽中的每一种的应答，所述辅助肽由多个HLA-DR分子限制; 4）获得关于在患有IV期黑素瘤的患者中每三个月加强疫苗接种是否可以维持对肽疫苗的免疫应答的初步数据;和5）在本研究的四个组中，获得关于对12肽疫苗的细胞免疫应答是否可以与临床结果相关的初步数据。