Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
基本信息
- 批准号:10246817
- 负责人:
- 金额:$ 91.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-07 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAcute T Cell LeukemiaAffinityAllogenicAreaBackBasic ScienceBispecific AntibodiesBone MarrowCD7 geneCRISPR/Cas technologyCXCL12 geneCXCR4 geneChemosensitizationClinical ResearchClinical TrialsComplicationDiseaseEffector CellEngraftmentFailureHematologic NeoplasmsHematopoiesisHematopoieticHematopoietic Stem Cell TransplantationHematopoietic stem cellsHomingIFNGR1 geneIL3RA geneIL8RB geneImmuneImmunotherapeutic agentImmunotherapyInfusion proceduresIntegrin alpha4beta1JAK1 geneJAK2 geneMalignant NeoplasmsMarrowMethodsMonoclonal AntibodiesNatural Killer CellsNatural regenerationPatientsPhase I Clinical TrialsPre-Clinical ModelProgressive DiseaseReagentRecurrenceRefractoryRelapseResearchSignal PathwaySystemT-LymphocyteTestingTimeTranslatingVascular Cell Adhesion Molecule-1acute myeloid leukemia cellbasebench to bedsidecancer genomicscareerchemotherapychimeric antigen receptor T cellscurative treatmentsdesignearly phase clinical trialefficacy testingfirst-in-humangraft vs host diseasegraft vs leukemia effectinhibitor/antagonistleukemialeukemia relapsenovelpreclinical studypreventprogramssuccesstargeted treatmenttransplantation therapy
项目摘要
PROJECT SUMMARY/ABSTRACT
Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only curative therapy for many patients
with hematologic malignancies and marrow failure states. Key obstacles to the success of HSCT include
collecting optimal numbers of hematopoietic stem/progenitor cells (HSPCs) capable of multilineage and
durable engraftment, control of graft-versus-host disease (GvHD), and treating disease recurrence both before
and especially after HSCT. I have focused my career over the last 20 years on overcoming these three
obstacles to HSCT through the use of a bench-to-bedside and back again research approach. My research
program over the next seven years will use our strengths in preclinical modeling, cancer genomics and the
design and execution of early phase clinical trials to (1) develop novel methods to target the hematopoietic
niche for optimal HSPC mobilization and chemosensitization of acute myeloid leukemia (AML), (2) target the
interferon gamma receptor (IFNγR) and IL-6R signaling pathways via use of selective and balanced JAK1/2
inhibitors to mitigate GvHD while maintaining graft vs. leukemia (GvL) after allo-HSCT, and (3) design and test
novel AML and T cell acute lymphoblastic leukemia (T-ALL) immunotherapeutics. Successful HSCT requires
the infusion of a sufficient number of HSPCs that are capable of homing to the bone marrow cavity and
regenerating durable trilineage hematopoiesis in a timely fashion. In our first research area, we will use new
strategies to enhance HSPC mobilization and leukemia chemosensitization via targeted modulation of the
CXCR4/CXCL12, VLA-4/VCAM-1 and/or CXCR2/Gro- axes. Managing the threat of GvHD while maximizing
the beneficial GvL effect would broaden the scope and usefulness of allo-HSCT. In our second major research
area we will perform preclinical and clinical studies to determine if targeting IFNγR, IL-6R, and/or JAK1/JAK2
can mitigate GvHD while maintaining GvL after T cell replete allo-HSCT. Finally, since many patients with AML
die from progressive disease after relapse, our third research area will develop and translate into early phase
clinical trials novel bi- and tri-specific monoclonal antibody reagents for the treatment of AML relapse before
and after HSCT. We will complete “first-in-man” phase I clinical trials of MGD006, a CD123xCD3 Dual Affinity
Re-Targeting (DART) bispecific antibody-based molecule and AMV564, a CD33xCD3 Tandem Diabody, in
patients with relapsed/refractory AML. While these trials are ongoing we are identifying novel targets for
immunotherapy in AML and testing the efficacy of new retargeting agents that engage either T cells, NK cells
or other immune effector cells to kill AML blasts expressing CD123, CD33, or the novel targets. Finally, since
no targeted therapies currently exist for T-ALL, we are developing allogeneic chimeric antigen receptor T cells
(CAR-T) to CD7, a T and NK cell marker that is highly expressed in T cell malignancies and in up to 40% of
AML cases. To prevent normal T cell fratricide and alloreactivity, we are using the CRISPR/Cas-9 system to
delete CD7 and the TCR chain from donor T cells prior to transduction with the CD7 CAR.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John F. Dipersio其他文献
John F. Dipersio的其他文献
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{{ truncateString('John F. Dipersio', 18)}}的其他基金
Project 6- Targeting AML using bispecific and antibody drug conjugates
项目 6 - 使用双特异性和抗体药物偶联物靶向 AML
- 批准号:
10615336 - 财政年份:2021
- 资助金额:
$ 91.46万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10469493 - 财政年份:2017
- 资助金额:
$ 91.46万 - 项目类别:
Pilot Projects and Trans-Network Activities Core
试点项目和跨网络活动核心
- 批准号:
9446709 - 财政年份:2017
- 资助金额:
$ 91.46万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10001462 - 财政年份:2017
- 资助金额:
$ 91.46万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10596338 - 财政年份:2017
- 资助金额:
$ 91.46万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
9765193 - 财政年份:2017
- 资助金额:
$ 91.46万 - 项目类别:
Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies
优化造血干细胞移植治疗血液恶性肿瘤
- 批准号:
10738323 - 财政年份:2017
- 资助金额:
$ 91.46万 - 项目类别:
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