IMPROVING CORD BLOOD TRANSPLANTATION

改善脐带血移植

• 批准号: 8931905
• 负责人: Catherine M. Bollard
• 金额: $ 263.07万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8931905
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adenoviruses; Adoptive Immunotherapy; Adoptive Transfer; Adult; Affinity; Allogenic; Antigens; B lymphoid malignancy; B-Lymphocytes; Blood; Blood Cells; Bone Marrow; Bone Marrow Transplantation; CD19 Antigens; CD19 gene; Cancer Immunology Science; Cancer Patient; Carbohydrates; Caucasians; Cause of Death; Cell Line; Cell surface; Cells; Child; Clinical; Clinical Trials; Cost Analysis; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Disadvantaged; Disease; Dose; Effectiveness; Engraftment; Enrollment; Epitopes; Family; Fucosyltransferase; Generations; Goals; HLA Antigens; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Homing; Hospitalization; Human Herpesvirus 4; Immune; Immunity; Immunology; Incidence; Infection; Infusion procedures; Institutional Review Boards; Instruction; Investigation; Laboratory Finding; Lymphocyte; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Marrow; Medical; Memory; Mesenchymal; Minority; Minority Groups; Myeloid Leukemia; Outcome; Patients; Phenotype; Population; Procedures; Records; Recurrence; Relapse; Research; Research Personnel; Research Project Grants; Residual Tumors; Selectins; Services; Source; Specificity; Stem cell transplant; Stem cells; Stromal Cells; Surface; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Time; Translating; Transplantation; Tumor Antigens; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Viral; Virus; Virus Diseases; Work; allotransplant; chimeric antigen receptor; design; graft failure; graft vs host disease; immunosuppressed; improved; leukemia treatment; multidisciplinary; neoplastic cell; novel; patient population; progenitor; programs; receptor; reconstitution; stem; stem cell biology; success; transplantation typing; tumor

DESCRIPTION (provided by applicant): The introduction of cord blood (CB) as an alternative graft source for patients without a human leukocyte antigen (HLA) matched donor was a clear breakthrough in the field of stem cell transplantation. Yet, consistently low doses of CB progenitor cells, resulting in delayed engraftment and immune reconstitution, unacceptable rates of infection, and high rates of relapse in CB recipients with cancer, have restricted the use of this procedure, especially in adults. Hence, the long-range goal of this proposal is to improve the outcome of CB transplantation by translating compelling laboratory findings into clinical trials, all within the framework of a multidisciplinary P01grant. The investigators in this program, representing 4 research projects and 4 Core services, have strong records of collaborative investigation in cancer immunology, viral immunology, CB transplantation, adoptive T-cell therapy, and stem cell biology - predicting extensive (and synergistic) interactions in pursuit of the goals outlined here. Project 1 will test the hypothesis that CB progenitors expanded on marrow stromal cells prior to infusion will engraft more rapidly than unmanipulated CB cells, and will further evaluate treatment of CB progenitors with fucosyltransferase as a novel means to improve bone marrow homing and engraftment. Project 2 asks if the infusion of CB-derived cytotoxic T cells (CTLs) targeting multiple viruses will provide broad protection against post-transplant viral infections, while Project 3 will direct the specificity of these virus-specific CTLs, using a chimeric antigen receptor (CAR), to the tumor-associated antigen CD19 in an effort to target malignant B cells as well as viruses. Finally, in Project 4, the ability of CB-derived CTLs to recognize the PR1 antigen aberrantly expressed on myeloid leukemias will be exploited to determine the feasibility and potential efficacy of PRI-specific CTL therapy in patients with myeloid leukemia undergoing CB transplantation. Ultimately, the information generated through this P01mechanism should yield a single, comprehensive plan of CB transplantation that will overcome most current limitations of this procedure, making it a realistic option for larger numbers of adult and childhood cancer patients.

描述（由申请人提供）：引入脐带血（CB）作为没有人类白细胞抗原（HLA）匹配供体的患者的替代移植来源是干细胞移植领域的一个明显突破。然而，持续低剂量的 CB 祖细胞导致移植和免疫重建延迟、不可接受的感染率以及患有癌症的 CB 接受者的高复发率，限制了这种手术的使用，特别是在成人中。因此，该提案的长期目标是通过将令人信服的实验室研究结果转化为临床试验来改善 CB 移植的结果，所有这些都在多学科 P01 拨款的框架内进行。该项目的研究人员代表 4 个研究项目和 4 个核心服务，在癌症免疫学、病毒免疫学、CB 移植、过继性 T 细胞疗法和干细胞生物学方面拥有良好的合作研究记录 - 预测在追求此处概述的目标。项目 1 将测试以下假设：输注前在骨髓基质细胞上扩增的 CB 祖细胞比未操作的 CB 细胞植入速度更快，并将进一步评估用岩藻糖基转移酶治疗 CB 祖细胞作为改善骨髓归巢和植入的新方法。项目 2 询问针对多种病毒的 CB 衍生细胞毒性 T 细胞 (CTL) 的输注是否将提供针对移植后病毒感染的广泛保护，而项目 3 将使用嵌合抗原受体指导这些病毒特异性 CTL 的特异性。 CAR）与肿瘤相关抗原 CD19 结合，以靶向恶性 B 细胞和病毒。最后，在项目 4 中，将利用 CB 衍生的 CTL 识别髓系白血病上异常表达的 PR1 抗原的能力，来确定 PRI 特异性 CTL 治疗接受 CB 移植的髓系白血病患者的可行性和潜在疗效。最终，通过这种 P01 机制生成的信息应该会产生一个单一、全面的 CB 移植计划，该计划将克服该程序当前的大多数限制，使其成为大量成人和儿童癌症患者的现实选择。