IMPROVING CORD BLOOD TRANSPLANTATION

改善脐带血移植

• 批准号: 8730459
• 负责人: Catherine M. Bollard
• 金额: $ 103.09万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730459
• 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; Caucasoid Race; Cause of Death; Cell Line; Cell surface; Cells; Child; Clinical; Clinical Trials; Commit; 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; 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物来源，这在干细胞移植领域是一个明显的突破。然而，始终低剂量的CB祖细胞会导致植入延迟和免疫结构，不可接受的感染率以及癌症患者CB受体的高复发率限制了此过程的使用，尤其是在成年人中。因此，该提案的远程目标是通过将引人注目的实验室发现转化为临床试验，以改善CB移植的结果，均在多学科P01Grant的框架内。该计划中的研究人员代表4个研究项目和4项核心服务，具有癌症免疫学，病毒免疫学，CB移植，收养T细胞疗法和干细胞生物学方面的合作调查记录，可以预测在此处概述的追求目标方面的广泛（和协同）相互作用。项目1将检验以下假设：在输注之前，在骨髓基质细胞上扩展的CB祖细胞比未经操纵的CB细胞更快地植入，并将进一步评估用岩藻糖基转移酶作为改善骨髓归巢和植入的新型手段对CB祖细胞的处理。项目2询问靶向多种病毒的CB衍生细胞毒性T细胞（CTL）是否会提供针对移植后病毒感染的广泛保护，而Project 3将使用嵌合抗原受体（CAR）指导这些病毒特异性CTL的特异性，以抗肿瘤抗体抗体抗体cd19，又是对肿瘤抗体的cd19。最后，在项目4中，将利用CB衍生的CTL识别在髓样白血病上异常表达的PR1抗原的能力，以确定PRI特异性CTL疗法对髓样白血病患者的可行性和潜在疗效。最终，通过这种P01机械产生的信息应产生一个单一的，全面的CB移植计划，该计划将克服该程序当前的大多数局限性，使其成为大量成人和儿童癌症患者的现实选择。