POTENTIATING & FOCUSING THE IMMUNE RESPONSE TO CANCER BY USE OF PEPTIDE ANTIGENS

增效

• 批准号: 7318392
• 负责人: DAVID A SCHEINBERG
• 金额: $ 24.75万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318392
• 关键词: Active Immunotherapy; Amino Acids; Animal Model; Animals; Antigens; Applications Grants; Autoantigens; Binding; Cancer Burden; Clinical; Clinical Trials; Development; Disease; Effectiveness; Epitopes; Goals; Grant; Hematopoietic Neoplasms; Human; Imino Acids; Immune response; Immunologic Monitoring; Immunotherapy; In Vitro; JAK2 gene; Knowledge; Malignant Neoplasms; Methods; Modeling; Multicenter Trials; Mus; Mutate; Mutation; Myeloproliferative disease; Oncogene Proteins; Oncogenes; Patients; Peptide Vaccines; Peptides; Phosphotransferases; Preclinical Testing; Preparation; Publishing; Relapse; Residual Cancers; Residual Tumors; Residual state; Risk; Role; Sampling; Stem cell transplant; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Time; Transgenic Model; Translating; Transplantation; Tumor Antigens; Vaccination; Vaccine Therapy; Vaccines; WT1 gene; Work; analog; base; cancer cell; cancer immunotherapy; clinical application; cross reactivity; design; graft vs host disease; immunogenicity; improved; leukemia; novel; peptide analog; peptide based vaccine; prototype; response; success; tumor; vaccine development

Optimal active immunotherapy of cancer should involve selectively potentiating the immune response to cancer specific antigens while reducing reactivity to self-antigens. Vaccine approaches are most likely to be effective in the setting of minimal cancer burden such as would occur after stem cell transplant (SCT). Therefore, the long-term goals of this project are to improve the effectiveness of SCT of hematopoietic neoplasms by safely increasing the immune response specifically directed at residual cancer cells using peptide vaccination. Much of the proposal focuses on WT1, a validated, commonly expressed tumor antigen. We also explore as a target the newly described mutated JAK2 kinase, responsible for many myeloproliferative disorders/These goals are reasonable because: 1) new understanding of the role of amino acid anchor motifs for MHC molecules in our target peptides and the strategic use of synthetic, heteroclitic, analog T cell epitopes. 2) the characterization of several peptide based vaccines for patients, including those to bcr/abl, WT-1, PR-1, and other oncogene associated targets as new cancer and leukemia associated tumor antigens. 3) the observation of clinical responses with the use of these peptide vaccines in patients with residual leukemia. Therefore, in this grant proposal we plan to extend our own work from the prior grant period and build on the published work of others into a better understanding of, and development of, specific immunotherapies directed to the oncogene products WT-1 and, for the first time, mutated JAK2 kinase. Previuosly, we focused on bcr/abl as a prototype target for vaccine therapy of CML and have progressed to multicenter trials. We build on this success here in new models directed at vaccine development against other important oncogene products. Aims 1 and 2 focus on WT1, a validated vaccine target found in many tumors and leukemias. Aim 1 is centered on discovery and characterization of novel WT-1 antigens. Aim 2A seeks to translate this knowledge in animals, in models of SCT and GVHD, and Aim 2B examines these antigens in humans. Aim 3 looks at the newly discovered, mutated JAK2 kinase, responsible for many myeloproliferative disorders, as a potential malignancy-specific target. There are important synergies between this project and project #4 of Richard O'Reilly in the development of the WT1 vaccine strategies. Relevance: Vaccines inducing or augmenting leukemia-selective T cell responses may reduce risk of relapse post transplant.

癌症的最佳主动免疫疗法应涉及选择性增强对的免疫反应 癌症特异性抗原，同时降低对自我抗原的反应性。疫苗方法最有可能是 在干细胞移植后（SCT）之后发生的最小癌症负担有效。 因此，该项目的长期目标是提高造血的SCT有效性 肿瘤通过安全增加针对残留癌细胞的免疫反应，使用 肽疫苗接种。大部分建议集中于WT1，这是经过验证的，通常表达的肿瘤 抗原。我们还作为目标探索了新描述的突变的JAK2激酶，负责许多 骨髓增生性疾病/这些目标是合理的，因为：1）对 用于靶肽中MHC分子的氨基酸锚定序和合成的战略使用， 杂色，类似T细胞表位。 2）对患者的几种基于肽的疫苗的表征， 包括新癌症和白血病的BCR/ABL，WT-1，PR-1和其他与癌基因相关的靶标 相关的肿瘤抗原。 3）在使用这些肽疫苗中观察临床反应 残留白血病的患者。因此，在这项赠款建议中，我们计划将自己的工作扩展到 以前的赠款期，并以他人的发表工作为基础，以更好地理解和发展 针对癌基因产品WT-1的特定免疫疗法，首次突变JAK2 激酶。 previuosly，我们专注于BCR/ABL作为CML疫苗治疗的原型靶标，并且具有 发展到多中心试验。我们在针对疫苗的新模型中以此成功为基础 针对其他重要的癌基产品的开发。目标1和2关注WT1，这是经过验证的疫苗 在许多肿瘤和白血病中发现的靶标。目标1集中在新颖的发现和表征上 WT-1抗原。 AIM 2A试图在SCT和GVHD模型中转化动物中的知识，并将其瞄准 2b检查了人类中的这些抗原。 AIM 3查看新发现的，突变的JAK2激酶， 负责许多骨髓增生性疾病，作为潜在的特定于恶性肿瘤的靶标。有 该项目与理查德·奥赖利（Richard O'Reilly）的项目＃4之间的重要协同作用在WT1的开发中 疫苗策略。相关性：诱导或增强白血病选择性T细胞反应的疫苗可能 减少移植后复发的风险。