NOVEL THERAPY FOR CHRONIC MYELOGENOUS LEUKEMIA

这项提议的总体目标是开发一种新的治疗方法 增强移植物抗白血病治疗慢性粒细胞白血病 效果(GVL)。移植物抗宿主病对骨髓移植的疗效至关重要 CML，但移植物抗宿主病的发病率和死亡率很高 (GVHD)对我们有效使用GVL的能力设置了限制。白介素1 受体拮抗剂(IL-1ra)对急性移植物抗宿主病的死亡率设定了限制 在小鼠模型中。此外，IL-1ra抑制CML祖细胞生长 在体外基于这些数据，一个两步的方法在发展 GVL增强是治疗慢性粒细胞白血病的一种新方法。第一，一个阶段 将进行试验以确定干扰素-α+ 供者淋巴细胞在慢性粒细胞白血病患者中提供GVL效应 异基因骨髓移植后复发。初步数据显示，这些 输液可引起血液学、细胞遗传学和分子遗传学 减刑。检测不到含有BRC/ABL转录本的细胞 使用一种非常灵敏的聚合酶链式反应(PCR)技术。这个 同样的技术是在很早的时候就发现复发的有效方法 阶段，并提供机会在以下时间启动GVL 肿瘤负担很低。为了实现这一目标， 将发展定量聚合酶链式反应技术。GVL效应很可能 与GvHD有关。来自临床前小鼠的初步数据 模型表明细胞因子失调在急性髓细胞白血病中起重要作用 白介素I和肿瘤坏死因子检测显示移植物抗宿主病的病理生理机制 急性移植物抗宿主病时皮肤和淋巴细胞中的α-信息。IL-1Ra是 是防治实验性移植物抗宿主病的非常有效的手段。 因此，这种方法的第二步是IL-2的I/II期试验。 对常规治疗无效的急性移植物抗宿主病患者的1ra 治疗。IL-1ra对这些患者的GvHD治疗特别有吸引力 患者，因为它在体外抑制CML祖细胞的生长，因此可能 增强GVL，而对正常造血无影响。在.期间 这些人类研究炎性细胞因子在诱导中的作用 并对GVHD和GVL的维持效应进行分析。这些研究 为最终目标奠定基础：使用干扰素-α(为了 减少慢性粒细胞白血病负担)、外周血淋巴细胞(诱导GVL)和 IL-1ra(控制GvHD和限制CML祖细胞增殖)AS 慢性粒细胞白血病的主要治疗方法。

The overall goal of this proposal is to develop a novel treatment for chronic myeloid leukemia (CML) by enhancing the graft-versus-leukemia effect (GvL). GvL is critical to the therapeutic efficacy of BMT for CML, but serious morbidity and mortality of graft-versus-host disease (GvHD) set limits on our ability to use Gvl effectively. Interleukin-1 receptor antagonist (IL-1ra) set limits on our mortality of acute GvHD in a murine model. In addition, IL-1ra inhibits CML progenitor growth in vitro Based on these data, a two-step approach in the development of Gvl enhancement as a new treatment for CML is proposed. First, a phase II trial will be performed to determine whether interferon-alpha plus donor lymphocytes provide a GvL effect in patients with CML that has relapsed after an allogeneic BMT. Preliminary data indicate that these infusions can induce hematologic, cytogenetic, and molecular genetic remissions. Cells containing brc/abl transcripts cannot be detected using a very sensitive polymerase chain reaction (PCR) technique. The same technique is an effective way to detect relapse at a very early stage, and provides the opportunity to initiate GvL at time when the tumor burden is very low. In order to accomplish this goal a quantitative PCR technique will be developed. The GvL effect is likely to be associated with GvHD. Preliminary data from the preclinical murine model suggest that cytokine dysregulation is important in the pathophysiology of GvHD, as demonstrated by the detection of IL-I and TNF alpha message in the skin and lymphocytes during acute GvHD. IL-1ra is a very effective means of preventing and treating experimental GvHD. Therefore, the second step to this approach is a phase I/II trial of IL- 1ra in patients with acute GvHD that is unresponsive to conventional treatment. IL-1ra is particularly attractive therapy for GvHD in these patients because it inhibits CML progenitor growth in vitro, and thus may enhance GvL, while having no effect on normal hematopoiesis. During these human studies the role of inflammatory cytokines in the induction and maintenance of GvHD and GvL effects will be analyzed. These studies lay the groundwork for the final goal: to use interferon-alpha (to reduce the CML burden), peripheral blood lymphocytes (to induce GvL) and IL-1ra (to control GvHD and limit CML progenitor proliferation) as primary therapy for CML.