Targeting Alloreactivity for Leukemia Eradication

针对白血病根除的同种异体反应性

• 批准号: 8277822
• 负责人: STANLEY R. RIDDELL
• 金额: $ 56.18万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277822
• 关键词: Acute leukemia; Alleles; Allogenic; Animal Model; Animals; Antigen Targeting; Antigens; Biological Models; CD8B1 gene; Cell Culture Techniques; Cell Lineage; Cell Transplantation; Cell Transplants; Cells; Cessation of life; Dose; Engineering; Engraftment; Epithelium; Frequencies; Genes; Hematopoietic; Hematopoietic Stem Cell Transplantation; Human; Immune; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Kinetics; Leukemic Cell; Malignant Neoplasms; Mediating; Minor; Minor Histocompatibility Antigens; Molecular; Pathogenesis; Patients; Peptides; Peripheral Blood Stem Cell; Pharmaceutical Preparations; Phenotype; Population; Public Health; Regimen; Relapse; Research; SELL gene; Siblings; Stem cell transplant; Stem cells; T cell response; T memory cell; T-Cell Depletion; T-Lymphocyte; Transplant Recipients; Transplantation; Vaccination; adult leukemia; base; gene discovery; graft vs host disease; improved; leukemia; novel; novel strategies; pathogen; progenitor; reconstitution; response; selective expression; tumor

6. Targeting Alloreactivity for Leukemia Eradication The eradication of leukemia after allogeneic hematopoietic stem cell transplantation (HCT) is in part mediated by T cells and represents a remarkable demonstration of the curative potential of immune-based therapy for human malignancy. There is substantial evidence that the immunologically mediated graft versus leukemia (GVL) effect results from recognition of leukemic cells by donor T cells specific for recipient minor histoco.mpatibility antigens. Unfortunately, T cell responses to minor histocompatibility antigens can also cause GVHD, and it has been difficult to segregate the GVL effect from GVHD. The discovery of minor histocompatibility antigens that are selectively expressed on leukemic cells and not on epithelium is providing new opportunities to augment the GVL effect of allogeneic HCT. However, implementing targeted immunotherapy in patients who receive unmodified allogeneic stem cell transplants and require the administration of immunosuppressive drugs post transplant has proven challenging. The discovery that naTve T cells in the stem cell inoculum are responsible for GVHD has provided the opportunity for manipulation of allogeneic hematopoietic cell grafts to remove this subset of cells and potentially reduce GVHD. The objectives of this project are to discover minor histocompatibility antigens that are targets for a selective GVL effect and to evaluate engineering the stem cell graft to remove naTve donor T cells that cause GVHD to provide a platform that enables selective targeting of allogeneic determinants on leukemic cells to promote an enduring GVL response. The specific aims are: 1) To identify genes that encode novel human minor histocompatibility antigens presented by leukemic cells and recognized by CD8+T-cells. 2) To determine whether transplantation of stem cell grafts depleted of halve T cells reduces graft versus host disease in HLA identical sibling stem cell transplant recipients with acute leukemia. 3) To determine if vaccination of allogeneic HCT donors with minor histocompatibility antigens is safe and elicits a specific T-cell response. Relevance of this research to public health: Allogeneic hematopoietic cell transplantation (HCT) canbe curative for many malignancies that are otherwise incurable and is used to treat thousands of patients each year. Graft versus host disease and relapse of the malignancy are the two most frequent complications that contribute to patient suffering and death after allogeneic HCT. The studies in this proposal are aimed at discovering the cellular and molecular mechanisms by which HCT eliminates tumors and developing safer and more effective transplant regimens.

6.靶向同种异体反应性用于根除白血病 异基因造血干细胞移植(HCT)后白血病的根除部分是 由T细胞介导，是免疫基础治疗潜力的显著例证 人类恶性疾病的治疗。有大量证据表明，免疫介导的移植物抗 白血病(GVL)效应是供者对受体小T细胞识别白血病细胞的结果 组织相容性抗原。不幸的是，T细胞对次要组织相容性抗原的反应也可以 导致GVHD，而且很难将GVL效应与GVHD分开。未成年人的发现 在白血病细胞上而不是在上皮细胞上选择性表达的组织相容性抗原是 为增强异基因血细胞移植的GVL效应提供了新的机会。然而，实施有针对性的 接受未经修饰的异基因干细胞移植患者的免疫治疗 事实证明，移植后免疫抑制药物的管理具有挑战性。NATve的发现 干细胞接种中的T细胞负责为GVHD提供了操控的机会 异基因造血细胞移植可以去除这部分细胞，并有可能减少移植物抗宿主病。这个 该项目的目标是发现作为选择性GVL靶点的次要组织相容性抗原 效果和评价工程干细胞移植去除NATve供者T细胞导致移植物抗宿主病 提供一个平台，能够选择性地靶向白血病细胞上的同种异体决定簇，以促进 GVL持久的回应。具体目标是： 1)鉴定编码白血病细胞呈递的新的人类次要组织相容抗原的基因 并被CD8+T细胞识别。 2)确定去除一半T细胞的干细胞移植是否会降低移植物抗 急性白血病的人类白细胞抗原相合同胞干细胞移植受者的宿主疾病。 3)确定组织相容性较差的同种异体血细胞移植供者接种疫苗是否安全 会引起特定的T细胞反应。 这项研究与公共卫生的相关性：异基因造血细胞移植(HCT)可以 治愈许多原本无法治愈的恶性肿瘤，每个人都被用来治疗数千名患者 年。移植物抗宿主病和恶性肿瘤复发是最常见的两种并发症 导致同种异体血细胞移植后患者痛苦和死亡。这项建议中的研究旨在 发现红细胞压积消除肿瘤和发展更安全的细胞和分子机制 以及更有效的移植方案。