Allogeneic stem cell transplant with grafts depleted of naive T cells for leukemi

使用去除初始 T 细胞的移植物进行同种异体干细胞移植治疗白血病

基本信息

批准号：
8298997
负责人：
Marie Bleakley
金额：
$ 17.01万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-08 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298997
关键词：
Acute Graft Versus Host Disease Acute leukemia Adoptive Immunotherapy Adoptive Transfer Alleles Allogenic Animals Antigens Binding Blood typing procedure Bone Marrow CD8B1 gene Cells Clinic Clinical Clinical Research Clinical Trials Conduct Clinical Trials Cytolysis Cytotoxic T-Lymphocytes Development Disease-Free Survival Donor Lymphocyte Infusion Dysmyelopoietic Syndromes Engraftment Enrollment Environment Evaluation Excision Flow Cytometry Foundations Fred Hutchinson Cancer Research Center Funding Future Generations Genes Genetic Goals Health Hematopoietic Hematopoietic Stem Cell Transplantation Histocompatibility Human Immune Immunity Immunobiology Immunologic Monitoring Immunology Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In Vitro Incidence Kinetics Laboratories Libraries Life Mediating Mentors Minor Modality Modeling Mus NOD/SCID mouse Opportunistic Infections Patients Peptides Peripheral Blood Stem Cell Pharmacotherapy Phase Prevention Principal Investigator Protocols documentation Recovery Relapse Research Research Activity Research Personnel Severities Siblings Staining method Stains Stem cell transplant Stem cells T memory cell T-Cell Depletion T-Lymphocyte Testing Tissues Toxic effect Training Training Activity Translating Translational Research Transplant Recipients Transplantation Vaccines Viral bacterial H antigen career cohort design experience genetic linkage analysis genome wide association study graft vs host disease human stem cells human study improved insight leukemia non-genetic novel novel strategies pathogen peripheral blood phase 2 study prevent progenitor reconstitution research study selective expression skills

项目摘要

DESCRIPTION (provided by applicant): The candidate's career goal is to become a principal investigator of a translational immunology laboratory that will develop new approaches to improve the disease-free survival of patients with leukemia that receive allogeneic hematopoietic stem cell transplantation (HCT). Specifically, the candidate aspires to develop immunotherapies to augment the graft versus leukemia (GVL) effect and thereby reduce the rates of relapse following HCT, and strategies to reduce the life-threatening immunological complications of HCT including graft versus host disease (GVHD). In the immediate term, the candidate aims to gain experience in translating her research to the clinic as the Principal Investigator of the clinical trial entitled "A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells from Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD (FHCRC Protocol 2222)", to develop further skills in antigen identification, and to become independent in designing, conducting, interpreting and funding her research. The research activities planned include the conduct and evaluation of the clinical trial of naive T cell depletion and associated immune reconstitution studies, and antigen discovery studies to generate a library of human minor histocompatibility (H) antigens. The candidate will obtain training in clinical trials, advanced flow cytometry, statistical analysis of immune monitoring, genetic linkage analysis and genome-wide association studies. The research and training activities will be primarily conducted at the Fred Hutchinson Cancer Research Center which is a superb environment for translational and clinical research, particularly in the field of HCT. The candidate will be mentored by Dr. Stanley Riddell, an experienced and successful mentor who has a distinguished career in the fields of translational immunology, immunotherapy and HCT. The applicant participated in all phases of development of the clinical trial, which is a novel, first-in-human study that will provide insights into the immunobiology of GVHD and the recovery of protective T cell immunity in recipients of stem cell grafts that contain a limited number of memory T cells. This approach may result in a new modality for allogeneic HCT with less GVHD and better immune reconstitution. The studies proposed in Aim 3 will employ new strategies for minor H antigen discovery and assist in laying the foundation for future immunotherapeutic approaches to the problem of relapse of leukemia after HCT. The specific aims are: 1. To determine whether transplantation of stem cell grafts depleted of TN is safe and reduces GVHD in HLA identical related donor stem cell transplant recipients. 2. To evaluate reconstitution of pathogen-specific TM and TN cells in recipients of HLA matched related stem cell grafts depleted of TN. 3. To develop a library of novel minor H antigens that are expressed selectively on hematopoietic cells including acute leukemia and presented in association with prevalent HLA alleles.

描述（由申请人提供）：候选人的职业目标是成为转化免疫学实验室的首席研究员，该实验室将开发新方法来提高接受同种异体造血干细胞移植（HCT）的白血病患者的无病生存率。具体来说，候选人渴望开发免疫疗法来增强移植物抗白血病（GVL）效应，从而降低 HCT 后的复发率，并制定策略来减少 HCT 危及生命的免疫并发症，包括移植物抗宿主病（GVHD）。在短期内，候选人的目标是作为题为“同种异体外周血干细胞移植物选择性去除 CD45RA+ T 细胞的多中心 II 期研究”临床试验的首席研究员，获得将其研究成果转化为临床的经验。 GVHD 的预防（FHCRC 方案 2222）”，以进一步发展抗原鉴定的技能，并独立设计、进行、解释和资助她的研究。计划的研究活动包括进行和评估初始 T 细胞耗竭和相关免疫重建研究的临床试验，以及生成人类次要组织相容性 (H) 抗原库的抗原发现研究。候选人将接受临床试验、高级流式细胞术、免疫监测统计分析、遗传连锁分析和全基因组关联研究方面的培训。研究和培训活动将主要在 Fred Hutchinson 癌症研究中心进行，该中心为转化和临床研究（尤其是 HCT 领域）提供了绝佳的环境。候选人将得到 Stanley Riddell 博士的指导，他是一位经验丰富且成功的导师，在转化免疫学、免疫治疗和 HCT 领域拥有杰出的职业生涯。申请人参与了临床试验开发的所有阶段，这是一项新颖的、首次人体研究，将深入了解 GVHD 的免疫生物学以及干细胞移植物受者保护性 T 细胞免疫的恢复。记忆T细胞数量有限。这种方法可能会带来一种新的同种异体 HCT 模式，具有更少的 GVHD 和更好的免疫重建。目标 3 中提出的研究将采用新策略来发现次要 H 抗原，并有助于为未来针对 HCT 后白血病复发问题的免疫治疗方法奠定基础。具体目标是： 1. 确定去除TN的干细胞移植物的移植是否安全，并降低HLA相同相关供体干细胞移植受者的GVHD。 2. 评估 HLA 匹配的相关干细胞移植物（去除 TN）的受者体内病原体特异性 TM 和 TN 细胞的重建。 3. 开发一个新型次要 H 抗原文库，该抗原在包括急性白血病在内的造血细胞上选择性表达，并与常见的 HLA 等位基因相关。