Hematopoietic Chimerism after Stem Cell Allografts

干细胞同种异体移植后的造血嵌合

基本信息

批准号：
8919997
负责人：
BRENDA MARIE SANDMAIER
金额：
$ 201.91万
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：
2000
资助国家：
美国
起止时间：
2000-03-31 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8919997
关键词：
Accounting Acute Graft Versus Host Disease Acute leukemia Address Adoptive Immunotherapy Allogenic Allografting Astatine B lymphoid malignancy Canis familiaris Cell Therapy Cell Transplants Chimerism Clinical Comorbidity Coupled Cyclophosphamide Cyclosporine Data Analyses Deposition Development Disease Dose Dysmyelopoietic Syndromes Elderly Failure Funding Gene-Modified Goals Graft-Versus-Tumor Induction Grant Health Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms Hour Immunosuppression Incidence Infection Infusion procedures Label Life Link Lymphoma Malignant Neoplasms Malignant lymphoid neoplasm Maximum Tolerated Dose Methotrexate Modeling Monoclonal Antibodies Natural Killer Cells Outcome PTPRC gene Patient risk Patients Pharmaceutical Preparations Procedures Protocols documentation Radial Radioisotopes Recurrent disease Regimen Regulatory T-Lymphocyte Relapse Risk Stem cells System T-Cell Activation T-Lymphocyte Therapeutic immunosuppression Translating Transplant Recipients Transplantation Treatment Failure Tumor Burden Whole-Body Irradiation base caspase-9 chronic graft versus host disease clinically relevant conditioning disorder prevention fludarabine graft vs host disease hematopoietic cell transplantation immune function leukemia/lymphoma mortality novel strategies pre-clinical preclinical study prevent success suicide gene tool treatment strategy tumor eradication

项目摘要

DESCRIPTION (provided by applicant): More than 1,850 elderly or medically infirm patients with advanced hematologic malignancies have received HLA-matched related or unrelated or HLA-haploidentical hematopoietic cell transplantation (HCT) on reduced- intensity conditioning regimens that were translated from canine studies under this grant. While overall 5-year survivals were encouraging, we identified two problems that accounted for nearly all of the treatment failures: non-relapse mortality (NRM) from graft-versus-host-disease (GVHD)-related causes and relapse-related mortality. Moreover, acute GVHD did not convey GVT effects. In contrast, chronic GVHD showed significant GVT effects; however, this benefit was offset by increased NRM. These findings set the theme for the current grant. We propose three projects, one preclinical and two clinical, which focus on reducing GVHD-related NRM and relapse mortality. The theme of the preclinical Project 1 is to minimize GVHD-related NRM. We will use a DLA-mismatched canine model that has served to develop nearly all of our GVHD prevention and treatment used clinically. Aim 1 will focus on preventing acute GVHD, and Aim 2 proposes new treatment strategies for chronic GVHD. Developing GVHD is consistent with T-cell activation despite standard immunosuppression. We have generated or identified monoclonal antibodies (mAbs) specific for canine T-cell regulatory molecules. Guided by the results of linked mechanistic studies, we will use the mAbs to block T-cell costimulation and/or downregulate or eliminate activated T-cells. We hypothesize that the current high incidence of acute GVHD can be reduced and that chronic GVHD can be treated more effectively, reducing both the duration of the current long-term immunosuppressive therapy (median 2.5 years) for transplanted patients and the risk of fatal infections. The clinical Projects 2 and 3 address relapse in patients with advanced acute leukemias and myelodysplasias (Project 2) and B-cell malignancies (Project 3) as well as extending allogeneic HCT to include patients who lack HLA-matched donors. Both projects propose dose-escalation studies for HLA-matched HCT recipients using an anti-CD45 mAb coupled to an alpha-emitting radionuclide, astatine-211 (211At), in addition to the standard fludarabine (FLU)/2Gy total body irradiation (TBI) conditioning regimen. This novel approach is based on extensive preclinical studies in our canine model. We anticipate a significant reduction in pretransplant tumor burden from the addition of the 211At-labeled mAb and, thus, a corresponding reduction in relapse risk after HCT. Both projects will also address the relapse problem in HLA-haploidentical recipients. Project 2 proposes dose-escalation studies with 211At-labeled anti-CD45 mAb in addition to FLU/cyclophosphamide/2Gy TBI conditioning. Project 3 proposes a study of natural killer cell infusions from the HLA-haploidentical donors after reduced-intensity conditioning. A concurrent trial after myeloablative conditioning will study augmentation of HLA-haploidentical HCT with gene-modified T-cells.

描述（由申请人提供）：超过1,850名患有晚期血液系统恶性肿瘤的老年人或医学弱势疾病患者已接受HLA匹配的相关或无关的或无关的或HLA-HAPLOCOIDICAL造血细胞移植（HCT），这些造血细胞移植（HCT）在降低的强度调节方案上从罐头研究中转化为这项拨款。尽管总体5年生存令人鼓舞，但我们确定了几乎所有治疗失败的问题：从移植物与宿主 - 宿主 - 疾病（GVHD）相关的原因和与复发相关的死亡率的非释放死亡率（NRM）。此外，急性GVHD没有传达GVT效应。相反，慢性GVHD显示出明显的GVT效应。但是，这种好处被NRM的增加所抵消。这些发现为当前赠款设定了主题。我们提出了三个项目，一个项目，一个临床前和两个临床，这些项目的重点是降低与GVHD相关的NRM和复发死亡率。临床前项目1的主题是最大程度地减少与GVHD相关的NRM。我们将使用DLA不匹配的犬模型，该模型几乎可以开发我们的所有GVHD预防和临床上使用的治疗。 AIM 1将专注于防止急性GVHD，AIM 2提出了针对慢性GVHD的新治疗策略。尽管标准免疫抑制，开发GVHD仍与T细胞激活一致。我们已经生成或鉴定出针对犬T细胞调节分子的单克隆抗体（MAB）。在链接的机械研究结果的指导下，我们将使用mAB阻止T细胞共刺激和/或下调或消除活化的T细胞。我们假设可以降低当前急性GVHD的高发病率，并且可以更有效地治疗慢性GVHD，从而减少了当前长期免疫抑制治疗的持续时间（中位2.5年），用于移植的患者和致命感染的风险。临床项目2和3解决了晚期急性白血病和骨髓增生性肿瘤（项目2）和B细胞恶性肿瘤（项目3）的患者的复发，并将同种异体HCT扩展到包括缺乏HLA匹配供体的患者。这两个项目都提出了使用抗CD45 MAB与α发射放射性核素（Astatine-211（211AT））偶联的HLA匹配的HCT HCT受体的剂量降低研究，此外还包括标准的氟达滨（Fludarabine（Fludarabine）（Fludarabine（Flu）（TBI）标准氟达滨（TBI）状态（TBI）条件。这种新颖的方法基于我们犬类模型中广泛的临床前研究。我们预计，增加了211AT标记的MAB的移植前肿瘤负担会显着减少，因此，HCT后的复发风险相应减少。这两个项目还将解决HLA-HAPLOIDENTIC收件人中的复发问题。项目2除了流感/环磷酰胺/2GY TBI调节外，还提出了211AT标记的抗CD45 MAB的剂量降低研究。 Project 3提出了一项研究降低强度调节后HLA-Haploidentic供体的天然杀伤细胞输注。脊髓完善调节后的并发试验将研究使用基因修饰的T细胞增强HLA-HAPLOIDENIC HCT。