Hematopoietic Chimerism after Stem Cell Allografts

描述（由申请人提供）：超过1,850名老年或身体虚弱的晚期血液系统恶性肿瘤患者接受了hla匹配相关或不相关或hla -单倍体相同的造血细胞移植（HCT），采用低强度调节方案，这些方案来自于本资助下的犬类研究。虽然总体5年生存率令人鼓舞，但我们发现了两个几乎导致所有治疗失败的问题：移植物抗宿主病（GVHD）相关原因引起的非复发死亡率（NRM）和复发相关死亡率。此外，急性GVHD不表现GVT效应。相比之下，慢性GVHD表现出明显的GVT效应；然而，这种好处被增加的NRM所抵消。这些发现确定了当前赠款的主题。我们提出了三个项目，一个临床前和两个临床，重点是降低gvhd相关的NRM和复发死亡率。临床前项目1的主题是尽量减少与gvhd相关的NRM。我们将使用一种dla不匹配的犬类模型，该模型已用于开发几乎所有临床使用的GVHD预防和治疗。Aim 1将重点关注急性GVHD的预防，Aim 2将提出慢性GVHD的新治疗策略。尽管标准的免疫抑制，但GVHD的发展与t细胞活化是一致的。我们已经生成或鉴定了针对犬t细胞调节分子的单克隆抗体（mab）。在相关机制研究结果的指导下，我们将使用单克隆抗体来阻断t细胞共刺激和/或下调或消除活化的t细胞。我们假设可以降低目前急性GVHD的高发病率，并且可以更有效地治疗慢性GVHD，从而减少移植患者目前长期免疫抑制治疗的持续时间（中位2.5年）和致命感染的风险。临床项目2和3针对晚期急性白血病和骨髓增生异常（项目2）以及b细胞恶性肿瘤（项目3）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。这两个项目都建议在标准的氟达拉滨(FLU)/2Gy全身照射（TBI）治疗方案之外，使用抗cd45单抗偶联α -放射核素astatine-211 （211At）对hla匹配的HCT受体进行剂量递增研究。这种新颖的方法是基于广泛的临床前研究在我们的犬模型。我们预计，通过添加2111at标记的单抗，移植前肿瘤负担将显著减少，因此，HCT后复发风险也相应降低。这两个项目还将解决hla -单倍体受体的复发问题。项目2建议使用211at标记的抗cd45单抗进行剂量递增研究，此外还有FLU/环磷酰胺/2Gy TBI调理。项目3提出了一项研究自然杀伤细胞输注从hla -单倍体相同的供体后，降低强度条件。一项同时进行的骨髓清除后的试验将研究基因修饰t细胞对hla -单倍体相同HCT的增强作用。

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.