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
基本信息
- 批准号:8555384
- 负责人:
- 金额:$ 27.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-22 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAddressAdoptive Cell TransfersAdoptive ImmunotherapyAdoptive TransferAdultAffinityAllogenicAnimal ModelAntigen ReceptorsAntigen-Presenting CellsAntigensAntiviral AgentsApoptosisAutologousB-LymphocytesBioluminescenceBioreactorsBlast CellBlood CirculationBlood donorBone MarrowCD28 geneCD8-Positive T-LymphocytesCell CountCell TherapyCellsClinicalClinical Trials DesignCytolysisCytotoxic T-LymphocytesDendritic CellsDiseaseEngineeringEpitopesExposure toFrequenciesGene-ModifiedGenesGoalsHLA-A2 AntigenHematologic NeoplasmsHumanImageImmuneImmunotherapyIn VitroLymphocyteMediatingMemoryMethodsModificationMonoclonal AntibodiesMyeloproliferative diseaseNOD/SCID mouseOutcomePET/CT scanPatientsPeptidesPhase I Clinical TrialsPhenotypePhysiologic pulsePopulationPredispositionReceptor GeneRecurrent diseaseRelapseRiskSafetySiteSorting - Cell MovementSpecificityStem cell transplantSystemT cell therapyT-Cell ReceptorT-LymphocyteTestingTimeTissuesTransgenic OrganismsTransplantationTreatment FailureUmbilical Cord BloodUmbilical Cord Blood TransplantationVaccinesVirus Diseasesbaseblood productcytotoxicityeffective therapygraft vs host diseasehigh riskimprovedin vivoleukemialeukemic stem cellmouse modelperipheral bloodpre-clinicalpreventreceptor expressionreconstitutionresearch studytraffickingtransduction efficiencytreatment strategy
项目摘要
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.
对于无法获得合适的 HLA 匹配供体的血液恶性肿瘤患者,脐带血移植 (CBT) 是一种日益有效的治疗方法。如果能够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,就可以开发出更有效的免疫治疗策略。我们的长期目标是通过改造供体 T 细胞以增加 GVL 而不增加 GVHD,从而改善 AML 患者的 CBT 效果。我们假设靶向白血病相关抗原 (LAA) 的供体 T 细胞,例如 AML 上的 HLA-A2 限制性 PR1 肽,优先介导 GVL 活性而不是 GVHD,并且脐带血 (CB) 供体来源的 PR1 特异性细胞毒性 T 细胞淋巴细胞 (PR1-CTL) 可以在离体引出和扩增,用于临床选择性诱导 CBT 接受者的 GVL。因此,我们从 PR1 疫苗临床反应者中克隆了高亲和力和低亲和力的 PR1 特异性 T 细胞受体-αBeta (TCR) 异二聚体,它们可以转导到多克隆 T 细胞中,以重新定向抗原特异性并介导抗白血病作用。我们还生产了一种对 PR1/HLA-A2 (8F4) 的特定构象表位具有高亲和力的单克隆抗体,可介导针对急性髓系白血病 (AML) 的有效且特异性的细胞毒性,以及与 CD3zeta + CD28 融合的 8F4 的单链 Fv作为嵌合抗原受体(CAR),将用于对 T 细胞进行基因修饰以研究 GVL 效应。此外,CB中前体PR1-CTL的数量比成人外周血高约1000倍,并且CB PRI-CTL在体外可被激活和扩增5倍以上。基于这些进展,我们建议(1)通过比较(a)单个 CB 单位的细胞扩增,(b)来自多个供体的细胞纯化,确定一种最佳方法来离体诱导和扩增有效的 CB 衍生的 PR1-CTL ,(c)PR1-TCR-alphaBeta基因修饰,和(d)8F4-CAR基因修饰; (2) 使用异种小鼠模型在体内验证PR1-CTL对抗人AML的效力,研究AML对PR1-CTL的持久性和可能的耐受性诱导,并确定空间和时间上的GVL效应、持久性和可能的耐受性。使用生物发光和 PET/CT 成像对 CB 衍生的 PR1-CTL 进行耐受。最后,基于确定的最佳获得 PR1-CTL 的方法,我们将 (3) 测试 CB 衍生的 PR1-CTL 作为 CBT 后 AML 患者过继细胞疗法的临床可行性和安全性。
项目成果
期刊论文数量(0)
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{{ truncateString('JEFFREY J MOLLDREM', 18)}}的其他基金
Anit-PR1 Immune Therapy for Myeloid Leukemia
Anit-PR1 粒细胞白血病免疫治疗
- 批准号:
8499745 - 财政年份:2013
- 资助金额:
$ 27.88万 - 项目类别:
Cord Blood T Cell Therapy for Myeloid Malignancies
脐带血 T 细胞治疗骨髓恶性肿瘤
- 批准号:
10478146 - 财政年份:2011
- 资助金额:
$ 27.88万 - 项目类别:
Cord Blood T Cell Therapy for Myeloid Malignancies
脐带血 T 细胞治疗骨髓恶性肿瘤
- 批准号:
10247038 - 财政年份:2011
- 资助金额:
$ 27.88万 - 项目类别:
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 - 财政年份:2011
- 资助金额:
$ 27.88万 - 项目类别:
Proteinase 3-Derived Peptide Epitopes to Elicit Cytotoxic T Lymphocytes Targeting
蛋白酶 3 衍生的肽表位可引发细胞毒性 T 淋巴细胞靶向
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6942925 - 财政年份:2004
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$ 27.88万 - 项目类别:
Project 2: Anti-PR1 Immune Therapy for Myeloid Leukemia
项目2:髓系白血病的抗PR1免疫治疗
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10247505 - 财政年份:2003
- 资助金额:
$ 27.88万 - 项目类别:
Project 2: Anti-PR1 Immune Therapy for Myeloid Leukemia
项目2:髓系白血病的抗PR1免疫治疗
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10006813 - 财政年份:2003
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$ 27.88万 - 项目类别:
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低风险骨髓增生异常综合征的免疫治疗
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6328510 - 财政年份:2001
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$ 27.88万 - 项目类别:
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低风险骨髓增生异常综合征的免疫治疗
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6892850 - 财政年份:2001
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$ 27.88万 - 项目类别:
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