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. 针对白血病根除的同种异体反应性 异基因造血干细胞移植（HCT）后部分消除白血病 由 T 细胞介导，代表了基于免疫的治疗潜力的显着证明 治疗人类恶性肿瘤。有大量证据表明，免疫介导的移植物与 白血病 (GVL) 效应是由供体 T 细胞对受者未成年人特异性识别白血病细胞造成的 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会 引起 GVHD，并且很难将 GVL 效应与 GVHD 区分开来。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 为增强同种异体 HCT 的 GVL 效应提供了新的机会。然而，有针对性地实施 接受未经修饰的同种异体干细胞移植并需要免疫治疗的患者 事实证明，移植后施用免疫抑制药物具有挑战性。天真的发现 干细胞接种物中的 T 细胞负责 GVHD，这为操纵 同种异体造血细胞移植物可去除这部分细胞，并有可能减少 GVHD。这 该项目的目标是发现作为选择性 GVL 目标的次要组织相容性抗原 效果并评估干细胞移植物的工程设计以去除导致 GVHD 的天然供体 T 细胞 提供一个平台，能够选择性靶向白血病细胞上的同种异体决定簇，以促进 持久的 GVL 反应。具体目标是： 1) 鉴定编码白血病细胞呈递的新型人类次要组织相容性抗原的基因 并被 CD8+T 细胞识别。 2) 确定去除一半 T 细胞的干细胞移植物的移植是否会降低移植物对 患有急性白血病的 HLA 相同同胞干细胞移植受者的宿主疾病。 3) 确定对具有次要组织相容性抗原的同种异体 HCT 供体进行疫苗接种是否安全且 引发特定的 T 细胞反应。 这项研究与公共卫生的相关性：同种异体造血细胞移植（HCT）可以 可治愈许多无法治愈的恶性肿瘤，并已用于治疗数千名患者 年。移植物抗宿主病和恶性肿瘤复发是两种最常见的并发症 导致同种异体 HCT 后患者的痛苦和死亡。本提案中的研究旨在 发现HCT消除肿瘤的细胞和分子机制并开发更安全 以及更有效的移植方案。