Biology and Transplantation of the Hematopoietic Stem Cell
Biology and Transplantation of the Hematopoietic Stem Cell
批准号:
8931146
负责人:
John E. Wagner
金额:
$194.09万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1997
资助国家:
美国
项目状态:
已结题
起止时间:
1997-09-15 至 2020-08-31
关键词:
Acute Graft Versus Host DiseaseAddressAgeAllogenicAntibodiesAntigensB-LymphocytesBiologyBlast CellBloodCD19 geneCD34 geneCell TherapyCellsCessation of lifeClinical TrialsComorbidityCyclic GMPData CollectionDevelopmentDimerizationDoseDysmyelopoietic SyndromesEngineeringEnsureEpigenetic ProcessEquilibriumFCGR3B geneFailureGenerationsGenetic EngineeringGoalsGrantHealthHematopoieticHematopoietic NeoplasmsHematopoietic Stem Cell TransplantationHematopoietic SystemHematopoietic stem cellsHumanImmuneImmune systemImmunologic MemoryImmunotherapyIncidenceInfectionInfusion proceduresLifeLiteratureLongevityLymphoidMHC Class I GenesMaintenanceMalignant - descriptorMalignant NeoplasmsMarrowMediatingMemoryMorbidity - disease rateMyelogenousNatural Killer CellsNon-Hodgkin&aposs LymphomaOpportunistic InfectionsOrganOutcomePatientsPharmaceutical PreparationsPopulationPreventionProceduresProgram Research Project GrantsPropertyQuality of lifeRecoveryRecurrent diseaseRegimenRegulatory T-LymphocyteRelapseRelative (related person)Residual CancersResidual TumorsRiskSafetySamplingServicesSiblingsSignal TransductionSpeedStem cell transplantStem cellsT cell therapyT-LymphocyteT-Lymphocyte and Natural Killer CellTechnology TransferTissuesTranslationsTransplantationTreatment FailureUmbilical Cord BloodWorkbasecancer cellcellular engineeringchemoradiationchemotherapychimeric antigen receptorconditioningcytotoxicdisorder later incidence preventiongraft vs host diseasehigh riskimprovedin vivoinnovationinterestkillingsleukemiamortalitymouse modelneoplasm immunotherapyphase I trialpreventprogenitorprogramsreconstitutionself-renewalstemtooltransplantation medicinetrial designtumor
中文摘要
描述(申请人提供):淋巴-造血系统癌症是发病率和死亡率的主要原因,随着人口老龄化和更多的人在先前的癌症中存活下来,骨髓增生异常综合征和非霍奇金淋巴瘤的发病率不断上升。异基因造血干细胞移植(HSCT)对一部分常规化疗失败或已知失败风险较高的患者是治愈的。然而,这一潜在的挽救生命的程序在可获得性方面受到限制,本身就与发病率和死亡率的高风险有关,主要是由于免疫并发症,包括移植物抗宿主病(GVHD)和免疫重建缓慢。对于那些在移植治疗的直接风险中幸存下来的人来说,复发仍然是一个障碍。为了促进脐带血(UCBT)后淋巴-造血恢复,在项目1中,我们建议1)确定大剂量UCB CD34细胞对免疫重建速度的影响,2)优化T调节细胞的剂量以预防急性GVHD,3)优化胸腺前体细胞的体外扩增以加速免疫恢复。为了设计一种更安全和更有效的预防和治疗白血病复发的过继T细胞疗法,在项目2中,我们建议:1)证明药物调控的抗hCD19SFv嵌合抗原受体(CAR)表达的T细胞可以根除恶性CD19 B细胞,确定CAR的持久性是否依赖于肿瘤或宿主来源的B细胞抗原信号,并证明药物拮抗剂的输注可以通过阻止二聚体来迅速停止CAR信号;2)证明人类T干细胞可以被重新编程和基因修饰以表达CARS,为过继肿瘤免疫治疗提供自我更新的CAR-TSM细胞,以提高存活率。4)识别和验证TSM状态的基本调节因素,以进一步优化基于TSM的汽车治疗。为了设计一种安全和更有效的针对复发治疗的过继NK细胞疗法,在项目3中,我们建议1)确定具有强大而持久的抗白血病活性的适应性NK细胞分化的潜在机制,并在I期试验中诱导它们的扩张,以消除复发白血病患者的白血病母细胞,以及2)在UCBT后复发的CD33恶性肿瘤患者中使用双特异性杀伤分子(Bike)抗体优化NK激活和肿瘤靶向。这些策略中的每一种都是高度创新的,无论是单独还是联合使用,都有很大的希望克服以前限制生存的最重要的障碍-免疫功能低下和复发-以及继续我们长期持有的实现UCB在移植医学中的全部潜力的兴趣。
英文摘要
DESCRIPTION (provided by applicant): Cancers of the lympho-hematopoietic system are a major cause of morbidity and mortality, with an increasing incidence of myelodysplastic syndrome and non-Hodgkins Lymphoma as the population ages and greater numbers survive prior cancers. Allogeneic hematopoietic stem cell transplant (HSCT) is curative in a proportion of patients who otherwise fail conventional chemotherapy or are known to be high risk of failure. However, this potentially life-saving procedure is restricted in its availability and is itself associated with the high risks of morbidity and mortality, primarily from immunological complications, including graft-versus-host disease (GVHD), and slow immune reconstitution. For those that survive the immediate risks of transplant therapy, relapse is still an obstacle. Toward our goal of facilitating lympho-hematopoietic recovery after umbilical cord blood (UCBT), in Project 1, we propose to 1) determine the impact of large doses of UCB CD34+ cells on the pace of immune reconstitution, 2) optimize dosing T regulatory cells for prevention of acute GVHD, and 3) optimize ex vivo expansion of thymic progenitors for accelerating immune recovery. Toward our goal of engineering a safer and more effective adoptive T cell therapy for leukemia relapse prevention and treatment, in Project 2, we propose to 1) demonstrate that drug regulated anti-hCD19SFv chimeric antigen receptor (CAR) expressing T cells can eradicate malignant CD19+ B cells, determine whether CAR persistence is dependent upon tumor- or host- derived B cell antigenic signals, and demonstrate that infusion of drug antagonists can rapidly halt CAR signaling by precluding dimerization, 2) demonstrate that human T stem-memory (Tsm) cells can be reprogrammed and genetically modified to express CARs providing self-renewable CAR-Tsm cells for adoptive tumor immunotherapy with enhanced survival, and 4) identify and validate essential regulators of the Tsm state to further optimize Tsm-based CAR therapy. And, toward our goal of engineering a safe and more effective adoptive NK cell therapy for relapse treatment, in Project 3 we propose to 1) determine the mechanism underlying the differentiation of adaptive NK cells which have potent and long-lived anti-leukemia activity, and induce their expansion in a phase I trial to eliminate leukemic blasts in patients with relapsed leukemia, and 2) optimize NK activation and tumor-targeting using bispecific killer engager (BiKE) antibodies with a subsequent 'first-in-human' clinical trial in patients with relapsed CD33+ malignancy after UCBT. Each of these strategies is highly innovative with substantial promise individually and in combination for overcoming the most important barriers - immunoincompetence and relapse - previously limiting survival as well as continuing our long-held interest in realizing the full potential of UCB in transplant medicine.
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Enhancement of Lympho-Hematopoietic Recovery after UCBT
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批准号:8310799
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项目类别:
-
资助金额:$33.27万
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财政年份:2011
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负责人:John E. Wagner
-
依托单位:
Enhancement of Lympho-Hematopoietic Recovery after UCBT
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批准号:7917906
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项目类别:
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资助金额:$98.91万
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财政年份:2010
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负责人:John E. Wagner
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依托单位:
Transplant Biology & Therapy
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批准号:7944881
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项目类别:
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资助金额:$4.43万
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财政年份:2009
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负责人:John E. Wagner
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依托单位:
Enhancement of Lympho-Hematopoietic Recovery after UCBT
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批准号:6983709
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项目类别:
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资助金额:$27.07万
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财政年份:2005
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负责人:John E. Wagner
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依托单位:
Transplant Biology and Therapy
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批准号:10576848
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项目类别:
-
资助金额:$4.85万
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财政年份:1998
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负责人:John E. Wagner
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依托单位:
Transplant Biology and Therapy
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批准号:10333253
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项目类别:
-
资助金额:$4.85万
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财政年份:1998
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负责人:John E. Wagner
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依托单位:
Engineered CD4 Tregs Targeting B-ALL and AML
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批准号:10554605
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项目类别:
-
资助金额:$35.08万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Biology & Transplantation of the Human Stem Cell
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批准号:8533733
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项目类别:
-
资助金额:$204.23万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Administrative and Clinical Research Support Core
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批准号:10554608
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项目类别:
-
资助金额:$14.91万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Biology & Transplantation of the Human Stem Cell
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批准号:8725940
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项目类别:
-
资助金额:$206.48万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Biology & Transplantation of the Human Stem Cell
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批准号:8310807
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项目类别:
-
资助金额:$214.86万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Enhancement of Lympho-Hematopoietic Recovery after UCBT
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批准号:8533731
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项目类别:
-
资助金额:$0.93万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Biology and Transplantation of the Hematopoietic Stem Cell
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批准号:9769631
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项目类别:
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资助金额:$185.77万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Off-the-Shelf Immune Effector Cells for Hematological Malignancies
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批准号:10554604
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项目类别:
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资助金额:$210.15万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Biology and Transplantation of the Hematopoietic Stem Cell
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批准号:9338128
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项目类别:
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资助金额:$191.49万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
Administrative and Translational Research Support Core
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批准号:8931147
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项目类别:
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资助金额:$22.4万
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财政年份:1997
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负责人:John E. Wagner
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依托单位:
TRANSPLANT CENTER FOR UMBILICAL CORD STEM CELL
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批准号:6154505
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项目类别:
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资助金额:$0.0万
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财政年份:1996
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负责人:John E. Wagner
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依托单位:
TRANSPLANT CENTER FOR UMBILICAL CORD STEM CELL
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批准号:6258740
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项目类别:
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资助金额:$9.75万
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财政年份:1996
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负责人:John E. Wagner
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依托单位:
TRANSPLANT CENTER FOR UMBILICAL CORD STEM CELL
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批准号:2729797
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项目类别:
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资助金额:$5.07万
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财政年份:1996
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负责人:John E. Wagner
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依托单位:
TRANSPLANT CENTER FOR UMBILICAL CORD STEM CELL
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批准号:2549030
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项目类别:
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资助金额:$2.75万
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财政年份:1996
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负责人:John E. Wagner
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依托单位:
海外基金