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Biology and Transplantation of the Hematopoietic Stem Cell

Biology and Transplantation of the Hematopoietic Stem Cell
造血干细胞的生物学和移植
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

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中文摘要
翻译
描述(由申请人提供):淋巴造血系统癌症是发病率和死亡率的主要原因,随着人口老龄化和既往癌症存活人数的增加,骨髓增生异常综合征和非霍奇金淋巴瘤的发病率也在增加。异基因造血干细胞移植(HSCT)可以治愈一部分常规化疗失败或已知失败风险高的患者。然而,这种潜在的挽救生命的程序在其可用性方面受到限制,并且本身与发病率和死亡率的高风险相关,主要来自免疫并发症,包括移植物抗宿主病(GVHD)和缓慢的免疫重建。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。为了实现我们促进脐带血(UCBT)后淋巴-造血恢复的目标,在项目1中,我们建议1)确定大剂量UCB CD 34+细胞对免疫重建速度的影响,2)优化调节性T细胞的剂量以预防急性GVHD,3)优化胸腺祖细胞的体外扩增以加速免疫恢复。为了实现我们设计用于白血病复发预防和治疗的更安全和更有效的过继性T细胞疗法的目标,在项目2中,我们提出1)证明药物调节的表达抗hCD 19 SFv嵌合抗原受体(CAR)的T细胞可以根除恶性CD 19 + B细胞,确定CAR持续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通过排除二聚化而快速停止CAR信号传导,2)证明人T干细胞记忆(Tsm)细胞可被重编程和遗传修饰以表达汽车,从而为过继性肿瘤免疫治疗提供具有增强的存活率的可自我更新的CAR-Tsm细胞,和4)鉴定和验证Tsm状态的必需调节剂以进一步优化基于Tsm的CAR疗法。并且,为了实现我们设计用于复发治疗的安全且更有效的过继NK细胞疗法的目标,在项目3中,我们提出1)确定具有有效且长寿命的抗白血病活性的适应性NK细胞分化的潜在机制,并在I期试验中诱导其扩增以消除复发性白血病患者中的白血病原始细胞,和2)使用双特异性杀伤细胞因子(BiKE)抗体优化NK活化和肿瘤靶向,随后在UCBT后复发的CD 33+恶性肿瘤患者中进行“首次人体”临床试验。这些策略中的每一个都是高度创新的,单独和组合起来都有很大的希望克服最重要的障碍-免疫功能不全和复发-以前限制生存,并继续我们长期以来对实现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
  • 批准号:
    8310799
  • 项目类别:
  • 资助金额:
    $33.27万
  • 财政年份:
    2011
  • 负责人:
    John E. Wagner
  • 依托单位:
Enhancement of Lympho-Hematopoietic Recovery after UCBT
  • 批准号:
    7917906
  • 项目类别:
  • 资助金额:
    $98.91万
  • 财政年份:
    2010
  • 负责人:
    John E. Wagner
  • 依托单位:
Transplant Biology & Therapy
  • 批准号:
    7944881
  • 项目类别:
  • 资助金额:
    $4.43万
  • 财政年份:
    2009
  • 负责人:
    John E. Wagner
  • 依托单位:
Enhancement of Lympho-Hematopoietic Recovery after UCBT
  • 批准号:
    6983709
  • 项目类别:
  • 资助金额:
    $27.07万
  • 财政年份:
    2005
  • 负责人:
    John E. Wagner
  • 依托单位:
海外基金