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PR1-specific CB T cells for Patients with Myeloid Malignancies

PR1-specific CB T cells for Patients with Myeloid Malignancies
PR1 特异性 CB T 细胞治疗骨髓恶性肿瘤患者
批准号:
9340311
负责人:
JEFFREY J MOLLDREM
金额:
$4.6万
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-09-22 至 2018-08-31

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项目成果

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中文摘要
翻译
脐带血移植(CBT)是一种日益有效的治疗血液恶性肿瘤患者的合适的HLA匹配的供体是不可用的。如果能将介导移植物抗白血病(GVL)的T细胞与介导移植物抗宿主病(GVHD)的T细胞区分开来,就能开发出更有效的免疫治疗策略。我们的长期目标是通过工程化供体T细胞来增加GVL而不增加GVHD来改善AML患者的CBT结果。我们假设靶向白血病相关抗原(LAA)的供体T细胞,如AML上的HLA-A2限制性PR 1肽,优先介导GVL活性超过GVHD,并且脐带血(CB)供体来源的PR 1特异性细胞毒性T淋巴细胞(PR 1-CTL)可以体外诱导和扩增用于临床,以选择性诱导CBT受体中的GVL。因此,我们克隆了高和低亲和力PR 1特异性T细胞受体-α β(TCR)异源二聚体从PR 1疫苗临床反应,它可以被转导到多克隆T细胞重定向抗原特异性和介导的抗白血病作用。我们还产生了对PR 1/HLA-A2(8 F4)的特异性构象表位具有高亲和力的单克隆抗体,其介导针对急性髓性白血病(AML)的有效和特异性细胞毒性,并且与CD 3 zeta + CD 28融合的8 F4的单链Fv作为嵌合抗原受体(CAR)将用于基因修饰T细胞以研究GVL效应。此外,与成人外周血相比,CB中前体PR 1-CTL的数量高约1000倍,并且CB PR 1-CTL可以在体外活化和扩增超过5倍。基于这些进展,我们提出(1)通过比较(a)从单个CB单位的细胞扩增,(B)从多个供体的细胞纯化,(c)PR 1-TCR-α β基因修饰,和(d)8 F4-CAR基因修饰,来鉴定体外诱导和扩增有效的CB衍生的PR 1-CTL的最佳方法;(2)使用异种小鼠模型来验证PR 1-CTL在体内抗人AML的效力,以研究AML对PR 1-CTL的持久性和可能的耐受诱导,并确定空间和时间GVL效应、持久性、以及使用生物发光和PET/CT成像的CB衍生的PR 1-CTL的可能耐受性。最后,基于确定的最佳获得PR 1-CTL的方法,我们将(3)测试CB衍生的PR 1-CTL作为AML患者CBT后的过继细胞治疗的临床可行性和安全性。
英文摘要
Cord blood transplantation (CBT) is an increasingly effective treatment for patients with hematological malignancies for whom suitable HLA-matched donors are not available. If T cells that mediate graft verus leukemia (GVL) could be distinguished from those that mediate graft versus host disease (GVHD), more effective immunotherapy strategies could be developed. Our long-term goal is to improve the outcome of CBT for patients with AML by engineering donor T cells to increase GVL without increasing GVHD. We hypothesize that donor T-cells targeting leukemia-associated antigens (LAA), such as the HLA-A2-restricted PR1 peptide on AML, preferentially mediate GVL activity over GVHD and that cord blood (CB) donor-derived PR1-specific cytotoxic T lymphocytes (PR1-CTL) can be elicited and expanded ex vivo for clinical use to selectively induce GVL in CBT recipients. Thus, we have cloned high- and low-affinity PR1-specific T cell receptor-alphaBeta (TCR) heterodimers from PR1 vaccine clinical responders, which can be transduced into polyclonal T-cells to redirect antigen specificity and mediate antileukemic effects. We have also produced a monoclonal antibody with high affinity for a specific conformational epitope of PR1/HLA-A2 (8F4) that mediates potent and specific cytotoxicity against acute myeloid leukemia (AML), and a single chain Fv of 8F4 fused with CD3zeta + CD28 as a chimeric antigen receptor (CAR) will be used to gene modify T-cells to study GVL effects. In addition, the number of precursor PR1-CTL is ~1000-fold higher in CB compared to adult peripheral blood and CB PRI-CTL can be activated and expanded more than 5-fold in vitro. On the strength of these advances, we propose to (1) identify an optimal method to elicit and expand potent CB-derived PR1-CTL ex vivo by comparing (a) cell expansion from single CB units, (b) cell purification from multiple donors, (c) PR1-TCR-alphaBeta gene modification, and (d) 8F4-CAR gene modification; (2) use a xenogeneic mouse model to validate the potency of PR1-CTL against human AML in vivo to study the persistence and possible tolerance induction of PR1-CTL by AML, and to determine the spatial and temporal GVL effects, persistence, and possible tolerance of CB-derived PR1-CTL using bioluminescence and PET/CT imaging. Finally, based on the method identified to optimally obtain PR1-CTL, we will (3) test the clinical feasibility and safety of CB-derived PR1-CTL as adoptive cell therapy for AML patients after CBT.
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PR1-specific CB T cells for Patients with Myeloid Malignancies
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