Inhibiting STAT1 as a novel graft-versus-host/graft-versus-leukemia therapy

描述(申请人提供)：T细胞是非常有效的消除白血病儿童异基因造血干细胞移植(AllHSCT)后残留的癌细胞，通过移植物抗白血病(GVL)效应。T细胞通常通过干细胞移植或作为单独的供者淋巴细胞输注(DLI)输入患者。主要的限制是这些相同的T细胞也可以攻击和破坏患者的正常身体组织，导致移植物抗宿主病(GVHD)。移植物抗宿主病是异基因造血干细胞移植后发病率和死亡率的重要因素。虽然有多种药物可用于治疗GVHD，但这些药物也抑制了T细胞调节有益的GVL效应的能力。这项建议的长期目标是开发新的治疗方法，在成功预防GVHD的同时，保留异基因HSCT对GVL的好处。由于移植物抗宿主病产生炎症细胞因子，如干扰素γ，激活免疫系统，该项目将利用异基因造血干细胞移植的小鼠模型来抑制浆细胞样树突状细胞(PDCs)中的STAT1信号，以使异基因造血干细胞移植受者抵抗干扰素γ的影响。过继转移STAT1缺陷的pDC是一种新的细胞治疗方法，它将允许使用大剂量的DLI安全地治疗白血病，而不会导致GVHD。最后，它还将利用儿童白血病的相关异基因造血干细胞移植模型开发和筛选各种针对GVL活性的STAT1的已批准药物。最终目标是通过开发将导致白血病新疗法的研究来支持国家癌症研究所的研究重点。这项提议将为将针对STAT1的药物推向临床提供基础，作为一种提高异基因造血干细胞移植的安全性和有效性，并最终提高白血病患者存活率的手段。

DESCRIPTION (provided by applicant): T cells are very potent eliminators of residual cancer cells in children with leukemia after allogeneic hematopoietic stem cell transplant (alloHSCT) through the graft-versus-leukemia (GVL) effect. T cells are typically transfused into patients in the stem cell graft or as a separate donor lymphocyte infusion (DLI). The major limitation is that these same T cells can also attack and damage normal body tissues in the patient, causing graft-versus-host disease (GVHD). GVHD contributes to significant morbidity and mortality after alloHSCT. Although a variety of medications are available to treat GVHD, these medications also suppress the ability of T cells to mediate a beneficial GVL effect. The long-term objective of this proposal is to develop novel therapies that preserve the GVL benefit of alloHSCT while successfully preventing GVHD. Because GVHD produces inflammatory cytokines, such as gamma interferon (IFNγ), that activate the immune system, this project will utilize mouse models of alloHSCT to inhibit STAT1 signaling in plasmacytoid dendritic cells (pDCs) to make alloHSCT recipients resistant to the effects of IFNγ. Adoptively transferring STAT1-deficient pDCs, a novel cellular therapy, will allow the usage of a high dose of DLI to treat leukemia safely without causing GVHD. Lastly, it will also develop and screen a variety of approved drugs that target STAT1 on GVL activity using a relevant alloHSCT model with pediatric leukemia. The ultimate goal is to support the research priorities of the National Cancer Institute by developing research that will lead to novel therapies for leukemia. This proposal will provide the foundation for bringing drugs that target STAT1 forward to the clinic as a means of improving the safety and efficacy of alloHSCT, and ultimately improving survival in patients with leukemia.