Program Integration and management

摘要--总体 已有1850多名老年或身体虚弱的晚期血液系统恶性肿瘤患者接受了 低血缘或非血缘或半相合的造血细胞移植 强度调理疗法是根据这项拨款从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，几乎所有的治疗失败都是由两个问题造成的： 移植物抗宿主病(GVHD)相关原因和复发相关的无复发死亡率(NRM) 死亡率。此外，急性GVHD不传递GVT效应。相比之下，慢性移植物抗宿主病表现出显著的 GVT效应；然而，这一好处被NRM的增加所抵消。这些发现为当前的 格兰特。我们提出了三个项目，一个临床前项目和两个临床项目，重点是减少GVHD相关的NRM 和复发死亡率。 临床前项目1的主题是将GVHD相关的NRM降至最低。我们将使用不匹配的DLA 几乎所有临床使用的移植物抗宿主病的预防和治疗都是以犬为模型的。 目标1将侧重于预防急性移植物抗宿主病，目标2为慢性移植物抗宿主病提出新的治疗策略。 尽管有标准的免疫抑制，GVHD的发生与T细胞的激活是一致的。我们有 产生或鉴定针对犬T细胞调节分子的单抗。引导式 根据相关机制研究的结果，我们将使用单抗来阻断T细胞的共刺激和/或 下调或消除激活的T细胞。我们假设目前急性移植物抗宿主病的高发病率 可以减少，慢性移植物抗宿主病可以得到更有效的治疗，缩短 移植患者目前的长期免疫抑制治疗(中位数为2.5年)及其死亡风险 感染。临床方案2和3针对晚期急性白血病患者的复发和 骨髓发育不良(项目2)和B细胞恶性肿瘤(项目3)以及将异基因红细胞移植扩大到包括 缺乏人类白细胞抗原相合供者的患者。这两个项目都建议对人类白细胞抗原相合的红细胞移植进行剂量递增研究 此外，使用与α发射放射性核素-211(211At)偶联的抗CD45单抗的接受者 至标准氟达拉滨(Flu)/2GY全身照射(TBI)预适应方案。这种新的方法是 基于对我们的犬类模型的广泛的临床前研究。我们预计将大幅减少 移植前由于添加了标记的211At单抗而产生的肿瘤负担，因此相应地减少了 HCT后复发风险。这两个项目还将解决人类白细胞抗原半相合受者的复发问题。 项目2建议使用211At标记的抗CD45单抗进行剂量递增研究，除了 流感/环磷酰胺/2GY全脑损伤调理。项目3提出了一项自然杀伤细胞输注研究 低强度条件化处理后的单倍体相合供者。清髓术后的一项同期试验 条件化将研究用基因修饰的T细胞增强人类白细胞抗原单倍体相合的红细胞。

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.