Program Integration and management

摘要-总体 超过1，850名患有晚期恶性血液病的老年人或体弱患者接受了 HLA匹配的相关或无关或HLA半相合的造血细胞移植（HCT）， 强度调节方案是根据这项赠款下的犬类研究翻译而来的。虽然总体5年 尽管存活率令人鼓舞，但我们发现了两个问题，它们几乎是所有治疗失败的原因： 移植物抗宿主病（GVHD）相关原因和复发相关原因的非复发死亡率（NRM） mortality.此外，急性GVHD没有传达GVT效应。相比之下，慢性GVHD表现出显著的 GVT效应;然而，这种益处被NRM增加所抵消。这些发现为当前的 格兰特.我们提出了三个项目，一个临床前和两个临床，重点是减少GVHD相关的NRM 和复发死亡率。 临床前项目1的主题是尽量减少GVHD相关的NRM。我们将使用一个DLA不匹配的 犬模型，已用于开发我们几乎所有的GVHD预防和治疗临床使用。 目标1将侧重于预防急性GVHD，目标2提出了慢性GVHD的新治疗策略。 尽管有标准的免疫抑制，但发生GVHD与T细胞活化一致。我们有 产生或鉴定了对犬T细胞调节分子具有特异性的单克隆抗体（mAb）。指导 根据相关机制研究的结果，我们将使用mAb阻断T细胞共刺激和/或 下调或消除活化的T细胞。我们假设目前急性GVHD的高发病率 可以减少，慢性GVHD可以得到更有效的治疗，既减少了持续时间， 移植患者目前的长期免疫抑制治疗（中位数2.5年）和致命性风险 感染.临床项目2和3解决晚期急性白血病患者的复发问题， 骨髓增生异常（项目2）和B细胞恶性肿瘤（项目3）以及扩展同种异体HCT，以包括 缺乏HLA匹配供体的患者。这两个项目都建议对HLA匹配的HCT进行剂量递增研究 此外，使用与α发射放射性核素<$-211（211 At）偶联的抗CD 45 mAb的受者 标准氟达拉滨（FLU）/2Gy全身照射（TBI）预处理方案。这种新颖的方法是 基于我们的犬模型的广泛临床前研究。我们预计， 由于添加211 At标记的mAb，移植前肿瘤负荷降低，因此， HCT后复发风险。这两个项目还将解决HLA半相合接受者的复发问题。 项目2建议使用211 At标记的抗CD 45 mAb进行剂量递增研究， FLU/环磷酰胺/2Gy TBI处理。项目3提出了一项自然杀伤细胞输注的研究， HLA-半相合的供体在降低强度的条件作用之后。清髓治疗后的同期试验 预处理将研究用基因修饰的T细胞增加HLA-半相合HCT。

ABSTRACT - OVERALL 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.