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免疫反应 癌症特异性抗原，同时降低对自身抗原的反应性。疫苗方法最有可能是 可以有效地将癌症负担降至最低，例如干细胞移植（SCT）后可能发生的情况。 因此，该项目的长期目标是提高造血干细胞移植的有效性。 通过安全地增加专门针对残留癌细胞的免疫反应来治疗肿瘤 肽疫苗接种。该提案的大部分内容都集中在 WT1，一种经过验证的、普遍表达的肿瘤 抗原。我们还探索了新描述的突变 JAK2 激酶作为靶标，该激酶负责许多 骨髓增殖性疾病/这些目标是合理的，因为：1）对骨髓增殖性疾病的作用有了新的认识 我们的目标肽中 MHC 分子的氨基酸锚定基序以及合成、 异簇、类似的 T 细胞表位。 2) 几种针对患者的肽疫苗的特性， 包括与 bcr/abl、WT-1、PR-1 和其他癌基因相关靶点作为新癌症和白血病的靶点 相关肿瘤抗原。 3）观察使用这些肽疫苗的临床反应 残留白血病患者。因此，在这项拨款提案中，我们计划将我们自己的工作从 之前的资助期，并以其他人已发表的作品为基础，更好地理解和发展 针对癌基因产物 WT-1 和突变 JAK2 的特异性免疫疗法 激酶。此前，我们重点关注 bcr/abl 作为 CML 疫苗治疗的原型靶点，并已 进展到多中心试验。我们在此成功的基础上建立了针对疫苗的新模型 针对其他重要致癌基因产品的开发。目标 1 和 2 重点关注 WT1，一种经过验证的疫苗 在许多肿瘤和白血病中发现的靶点。目标 1 集中于小说的发现和表征 WT-1 抗原。 Aim 2A 旨在将这些知识转化为动物、SCT 和 GVHD 模型，以及 Aim 2B 检查人体中的这些抗原。目标 3 着眼于新发现的突变 JAK2 激酶， 作为潜在的恶性肿瘤特异性靶点，导致许多骨髓增殖性疾病。有 该项目与 Richard O'Reilly 的项目 #4 在 WT1 开发中具有重要的协同作用 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 降低移植后复发的风险。