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

抑制 STAT1 作为一种新型移植物抗宿主/移植物抗白血病疗法

基本信息

批准号：
9264486
负责人：
Christian Capitini
金额：
$ 17.87万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9264486
关键词：
Address Adoptive Transfer Adult Allogenic Antigen-Presenting Cells Antigens Bone Marrow Bone Marrow Transplantation Cell physiology Cell surface Cessation of life Child Childhood Leukemia Clinic Clinical Complex Dendritic Cells Donor Lymphocyte Infusion Dose Drug Targeting Drug usage Engineering Event Foundations Functional disorder Goals Hematopoietic Stem Cell Transplantation Immune Tolerance Immune system Immunologic Deficiency Syndromes Immunologics Immunosuppressive Agents Impairment Inflammatory Interferon Receptor Interferon Type II Interferons Interleukin-10 Mediating Modeling Morbidity - disease rate Mus National Cancer Institute Non-accidental Normal tissue morphology Pathway interactions Patients Pharmaceutical Preparations Phase Photopheresis Pre-B-Cell Leukemia Proliferating Recurrence Refractory Regimen Research Research Priority Research Support Residual Cancers Resistance Safety Signal Transduction Signaling Molecule Small Interfering RNA Stem cells Survival Rate T-Lymphocyte Testing Tissues Transcription Coactivator Transfusion Transplant Recipients Vaccines Work arm cancer cell cellular engineering chemotherapy clinically relevant cytokine cytotoxic cytotoxicity graft vs host disease high risk improved in vivo inhibitor/antagonist killings knock-down leukemia mortality mouse model new therapeutic target novel novel strategies novel therapeutics pediatric patients perforin prevent public health relevance response tumor

项目摘要

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.

描述（由申请人提供）：T细胞是白血病儿童在异基因造血干细胞移植（alloHSCT）后通过移植物抗白血病（GVL）效应消除残留癌细胞的非常有效的消除剂。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。主要的限制是这些相同的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）。GVHD导致alloHSCT后显著的发病率和死亡率。虽然有多种药物可用于治疗GVHD，但这些药物也抑制T细胞介导有益GVL效应的能力。该提案的长期目标是开发新的疗法，在成功预防GVHD的同时保留alloHSCT的GVL益处。由于GVHD产生激活免疫系统的炎性细胞因子，如γ干扰素（IFNγ），因此本项目将利用alloHSCT小鼠模型抑制浆细胞样树突状细胞（pDC）中的STAT 1信号传导，使alloHSCT受体对IFNγ的作用产生抗性。连续性转移STAT1缺陷型pDC，一种新的细胞疗法，将允许使用高剂量的DLI来安全地治疗白血病而不引起GVHD。最后，它还将开发和筛选各种批准的药物，这些药物使用相关的儿童白血病alloHSCT模型靶向GVL活性的STAT1。最终目标是通过开发研究来支持美国国家癌症研究所的研究重点，这些研究将导致白血病的新疗法。该提案将为将靶向STAT1的药物推向临床提供基础，作为提高alloHSCT安全性和有效性的一种手段，并最终提高白血病患者的生存率。