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

癌症的最佳主动免疫疗法应该包括选择性地增强免疫应答， 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 在最小癌症负荷的情况下是有效的，例如在干细胞移植（SCT）后会发生。 因此，本项目的长期目标是提高造血干细胞移植的效果 通过安全地增加特异性针对残留癌细胞的免疫应答， 肽疫苗接种大部分建议集中在WT 1上，这是一种经过验证的，通常表达的肿瘤 抗原的我们还探索了新描述的突变JAK 2激酶作为靶点，该激酶负责许多 骨髓增生性疾病/这些目标是合理的，因为：1）对骨髓增生性疾病的作用有了新的认识， 我们的靶肽中MHC分子的氨基酸锚基序和合成的， 异型的，类似的T细胞表位。2)用于患者的几种基于肽的疫苗的表征， 包括针对bcr/abl、WT-1、PR-1和其他癌基因相关靶点的新癌症和白血病 相关肿瘤抗原。3)使用这些肽疫苗的临床反应的观察， 残留白血病患者。因此，在这项资助提案中，我们计划将我们自己的工作从 以前的赠款期间，并建立在他人发表的工作，以更好地了解和发展 针对癌基因产物WT-1的特异性免疫疗法，以及首次突变的JAK 2 激酶。以前，我们把bcr/abl作为CML疫苗治疗的原型靶点， 进展为多中心试验。在此成功的基础上，我们开发了针对疫苗的新模型， 针对其他重要的癌基因产物的发展。目标1和2侧重于WT 1，一种经过验证的疫苗 在许多肿瘤和白血病中发现的靶点。目的1是集中在发现和表征的小说 WT-1抗原。目的2A试图在动物中，在SCT和GVHD模型中转化这些知识，并且目的2A试图在SCT和GVHD模型中转化这些知识。 2B检查人类中的这些抗原。目标3着眼于新发现的突变JAK 2激酶， 负责许多骨髓增生性疾病，作为一个潜在的恶性肿瘤特异性目标。有 该项目与Richard O 'Reilly在WT 1开发中的4号项目之间的重要协同作用 疫苗战略。相关性：诱导或增强白血病选择性T细胞应答的疫苗可能 降低移植后复发的风险。

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.