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

摘要 T细胞是白血病儿童异体移植后残留癌细胞的非常有效的清除剂 造血干细胞移植（alloHSCT）通过移植物抗白血病（GVL）效应。T细胞 通常在干细胞移植物中或作为单独的供体淋巴细胞输注（DLI）输注到患者体内。的 主要的局限性是这些相同的T细胞也可以攻击和损害患者的正常身体组织， 引起移植物抗宿主病（GVHD）。移植物抗宿主病在移植后导致显著的发病率和死亡率。 alloHSCT。尽管有多种药物可用于治疗GVHD，但这些药物也抑制了GVHD。 T细胞介导有益的GVL效应的能力。 这项提案的长期目标是开发新的治疗方法，保留GVL的好处， alloHSCT同时成功预防GVHD。由于GVHD产生炎性细胞因子，如 γ干扰素（IFN？），激活免疫系统，该项目将利用小鼠模型的alloHSCT 抑制浆细胞样树突状细胞（pDC）中的STAT1信号传导，使alloHSCT受体对 IFN的影响。连续性转移STAT1缺陷型pDC，一种新的细胞疗法，将允许使用 高剂量DLI安全治疗白血病而不引起GVHD。最后，它还将开发和筛选 使用儿科相关alloHSCT模型，研究了靶向STAT1对GVL活性的各种获批药物 白血病其最终目标是通过开发，支持国家癌症研究所的研究重点， 这一研究将为白血病带来新的治疗方法。这一提议将为 将靶向STAT1的药物作为改善alloHSCT安全性和有效性的手段推向临床，以及 最终提高白血病患者的生存率。

Abstract 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 (IFN¿), 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 IFN¿. 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.