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

描述（由申请人提供）：T细胞通过移植物抗白血病（GVL）效应，在异基因造血干细胞移植（alloHSCT）后的儿童白血病患者中，是非常有效的残余癌细胞的消除者。T细胞通常通过干细胞移植或作为单独的供体淋巴细胞输注（DLI）输注到患者体内。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）。同种异体造血干细胞移植后，GVHD导致显著的发病率和死亡率。尽管有多种药物可用于治疗GVHD，但这些药物也会抑制T细胞介导有益GVL作用的能力。该提案的长期目标是开发新的治疗方法，在成功预防GVHD的同时，保留同种异体造血干细胞移植的GVL益处。由于GVHD产生炎性细胞因子，如γ干扰素（IFNγ），激活免疫系统，本项目将利用同种异体造血干细胞小鼠模型抑制浆细胞样树突状细胞（pDCs）中的STAT1信号，使同种异体造血干细胞受体抵抗IFNγ的影响。过继性转移stat1缺陷的pDCs是一种新的细胞疗法，将允许使用高剂量的DLI安全地治疗白血病，而不会引起GVHD。最后，它还将开发和筛选各种已批准的药物，使用相关的儿童白血病同种异体造血干细胞模型靶向STAT1的GVL活性。最终目标是通过开发白血病新疗法的研究来支持国家癌症研究所的研究重点。这一建议将为将靶向STAT1的药物作为提高同种异体造血干细胞移植安全性和有效性的手段推向临床提供基础，并最终提高白血病患者的生存率。

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.