Adult Leukemia Research Center

成人白血病研究中心

基本信息

批准号：
9925047
负责人：
FREDERICK APPELBAUM
金额：
$ 399万
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：
1997
资助国家：
美国
起止时间：
1997-08-28 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925047
关键词：
Acute Acute Myelocytic Leukemia Acute T Cell Leukemia Acute leukemia Address Adoptive Cell Transfers Adoptive Immunotherapy Affinity Allogenic Autologous Behavior Biological Bone Marrow CD19 gene CD28 gene CD8-Positive T-Lymphocytes CD8B1 gene Categories Cells Clinical Complication Cyclophosphamide Disease Effectiveness Exposure to Failure Gene Transfer Gene-Modified Genetic Engineering Goals Hematologic Neoplasms In Vitro In complete remission Individual Infection Lead Learning Leukemic Cell Malignant - descriptor Malignant Neoplasms Membrane Methods Morbidity - disease rate Multiple Myeloma Myeloproliferative disease Non-Hodgkin&apos s Lymphoma Patients Pattern Peripheral Blood Lymphocyte Plasma Cells Pre-Clinical Model Prevention Program Research Project Grants Prophylactic treatment Quality of life Randomized Recurrence Relapse Research Residual Neoplasm Resistance Safety Signal Transduction T cell therapy T-Cell Receptor T-Lymphocyte Testing Therapeutic Therapeutic Agents Therapeutic immunosuppression Toxic effect Transplantation Treatment Failure Tumor Antigens WT1 gene adult leukemia cellular transduction chemotherapy chimeric antigen receptor chimeric antigen receptor T cells chronic graft versus host disease curative treatments disorder prevention engineered T cells experimental study genetically modified cells graft vs host disease graft vs leukemia effect hematopoietic cell transplantation immune reconstitution improved improved functioning in vivo insight lenalidomide mortality novel strategies novel therapeutics peripheral blood phase 2 study post-transplant prevent programs response standard of care success tool trafficking transplant survivor tumor

项目摘要

Project Summary/Abstract Overall The overall goal of this Program Project Grant is to develop improved curative therapies for patients with hematological malignancies focusing primarily on adoptive cell therapy and hematopoietic cell transplantation (HCT). Because HCT often offers the best chance for cure, approximately 70,000 patients worldwide received transplants for hematological malignancies last year. Disease recurrence post HCT is the leading cause of treatment failure. T cells engineered by gene transfer to express a synthetic T cell receptor (TCR) or chimeric antigen receptor (CAR) targeting a tumor-associated antigen have great potential as therapeutic agents, but there is much to learn about how to optimize effectiveness, eliminate toxicities and combine them with HCT. The objectives of this Program Project Grant are to develop effective T cell therapies for patients with the most common indication for allogeneic HCT, acute myeloid leukemia (AML), and autologous HCT, multiple myeloma, and to define the type of graft-versus-host disease (GVHD) prophylaxis that will best allow the use of adoptive T cell therapy post HCT. These objectives will be pursued in three interactive projects. Project 1 will explore the use of specific adoptive immunotherapy using high affinity WT1-specific TCR transduced T cells to treat patients with AML who have failed to achieve an initial complete response with conventional chemotherapy. In addition to determining the toxicity and efficacy of such treatment, this Project will test if cells derived from TN, TCM, of TEBV differ in their behavior, and will address features of TCR T cells and AML that lead to success or failure of treatment. Project 2 will evaluate the safety and efficacy of BCMA specific CAR T cells for treatment of patients with recurrent multiple myeloma. A direct comparison of CAR T cells containing two different co-stimulatory domains, CD28 versus 4-1BB, will be made to determine if they differ in efficacy or toxicity. Further experiments will explore methods to enhance the utility of BCMA CAR T cells including approaches to increase expression of BCMA on target cells or improve the function of CAR T cells by exposure to lenalidomide. In Project 3, two novel approaches to GVHD prophylaxis following peripheral blood HCT (TN cell depletion and post-HCT cyclophosphamide) will be compared to the current standard of care to determine which approach results in the highest percent of GVHD-free, relapse-free survival. Bone marrow and peripheral blood lymphocytes will be evaluated to determine immune reconstitution as well as factors that may best support subsequent adoptive immunotherapy. Success in the pursuit of the goals of this Program Project will provide powerful tools for treating AML and multiple myeloma, and should help define the best approach to GVHD prevention in the era of gene-modified T cells.

项目概要/摘要全面的该计划项目拨款的总体目标是为患有以下疾病的患者开发改进的治疗方法主要关注过继细胞治疗和造血细胞移植的血液恶性肿瘤（HCT）。由于 HCT 通常提供最佳治愈机会，全球约有 70,000 名患者接受了去年进行了血液恶性肿瘤移植手术。 HCT 后疾病复发是导致治疗失败。通过基因转移改造的 T 细胞可表达合成 T 细胞受体 (TCR) 或嵌合体靶向肿瘤相关抗原的抗原受体（CAR）作为治疗剂具有巨大的潜力，但是关于如何优化有效性、消除毒性并将其与 HCT 相结合，还有很多东西需要学习。该计划项目拨款的目标是为病情最严重的患者开发有效的 T 细胞疗法。同种异体 HCT、急性髓系白血病 (AML) 和自体 HCT 的常见适应症骨髓瘤，并定义移植物抗宿主病（GVHD）预防的类型，最好允许使用 HCT 后的过继性 T 细胞治疗。这些目标将通过三个互动项目来实现。项目 1 将探索使用高亲和力 WT1 特异性 TCR 进行特异性过继免疫治疗转导 T 细胞来治疗 AML 患者，这些患者未能达到初始完全缓解常规化疗。除了确定此类治疗的毒性和功效外，该项目将测试源自 TN、TCM 或 TEBV 的细胞在行为上是否存在差异，并将解决 TCR T 细胞的特征以及导致治疗成功或失败的 AML。项目2将评估BCMA的安全性和有效性特异性 CAR T 细胞用于治疗复发性多发性骨髓瘤患者。 CAR T 的直接比较含有两个不同共刺激结构域（CD28 与 4-1BB）的细胞将被用来确定它们是否功效或毒性不同。进一步的实验将探索增强 BCMA CAR T 效用的方法细胞，包括增加靶细胞上 BCMA 表达或改善 CAR T 功能的方法细胞暴露于来那度胺。在项目 3 中，以下两种新的 GVHD 预防方法外周血 HCT（TN 细胞去除和 HCT 后环磷酰胺）将与当前的进行比较护理标准，以确定哪种方法可实现最高比例的无 GVHD、无复发生存。将评估骨髓和外周血淋巴细胞以确定免疫重建以及最能支持后续过继免疫治疗的因素。追求成功该计划的目标将为治疗 AML 和多发性骨髓瘤提供强大的工具，并且应该帮助确定基因修饰 T 细胞时代预防 GVHD 的最佳方法。