Project 5 - Memory-like NK cell augmented hematopoietic cell transplantation for AML.
项目 5 - 记忆样 NK 细胞增强造血细胞移植治疗 AML。
基本信息
- 批准号:10931079
- 负责人:
- 金额:$ 23.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-03 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Myelocytic LeukemiaAddressAdoptive Cell TransfersAdoptive ImmunotherapyAgonistAllogenicBiologyBloodBone MarrowCell CountCell TherapyCellsCellular biologyCitrusClinicClinicalClinical ResearchClinical TrialsCombination immunotherapyCyclophosphamideCytometryDataDisease remissionDisease-Free SurvivalDoseEffectivenessEngraftmentEnvironmentEvaluable DiseaseExhibitsFutureGoalsHaptensHematopoieticHumanImmuneImmune systemImmunologyImmunotherapyIncidenceInterleukin-15Leukemic CellLicensingLigandsLongevityMediatingMemoryMethodsNK cell therapyNatural Killer Cell ImmunotherapyNatural Killer CellsNatural SelectionsOutcomePatientsPhasePhase II Clinical TrialsPhenotypePopulationProgression-Free SurvivalsPropertyReceptor CellRecurrent diseaseRefractoryRegimenRegulatory T-LymphocyteRelapseReportingResearchResidual stateResistanceSafetySpecialized Program of Research ExcellenceSpecificityT-LymphocyteTestingTranslatingTransplantationVirus Diseasesbiomarker identificationchronic graft versus host diseaseconditioningcostcytokineexperimental studyfirst-in-humangraft vs host diseasegraft vs leukemia effecthematopoietic cell transplantationhigh riskhuman studyimmunotherapy clinical trialsimprovedin vivoleukemialeukemia relapsemortalitymultidimensional datanovelolder patientphase 1 studyphase 2 studyprimary endpointresponseresponse biomarkersafety testingstandard caresuccesstranslational approachtumor
项目摘要
Project Summary/Abstract
The long-term goals of this project are to translate novel findings in the field of immunology into early phase
immunotherapy clinical trials for patients with leukemia. Allogeneic hematopoietic cell transplantation (HCT) is
a standard treatment for high-risk or relapsed AML and is potentially curative. However, major barriers to
success in older AML patients include 1) an inability to tolerate intensive conditioning, 2) disease relapse, 3)
graft-versus-host disease (GVHD), and 4) the lack of a suitable donor in many cases. One key immune player
in mediating the graft-versus-leukemia (GvL) effect that also potentially limits GVHD is the NK cell. We
hypothesize that new findings in NK cell biology can be translated to the clinic to improve the effectiveness and
tolerability of HCT in older AML patients.
Recent clinical studies have reported that HCT from an MHC-haploidentical donor (haplo-HCT) with
myeloablative conditioning regimens that incorporate post-HCT cyclophosphamide results in clinical outcomes
that are comparable to HCT from matched unrelated donors. However, one major obstacle to treating AML
patients with haplo-HCT is the large number of older patients that are only candidates for reduced-intensity
conditioning (RIC), which results in lower treatment-related mortality, but at the cost of a much higher incidence
of AML relapse, and thus far, poor long-term disease-free survival. To address this important hurdle in the field,
we will augment HCT with same-donor memory-like NK cell adoptive immunotherapy during the immediate
post-HCT period, to enhance GvL while potentially improving engraftment and minimizing GVHD.
Reports have recently identified that NK cells exhibit “memory-like” properties following combined cytokine
pre-activation. We and others have established that human memory-like NK cells respond robustly after a
second stimulation and have multiple anti-tumor properties. We have translated this into a cellular therapy for
relapsed/refractory (rel/ref) AML patients, and have completed a phase 1 study. However, one drawback of this
allogeneic NK cell therapy is its rejection by the recipient's recovering immune system after 2-3 weeks,
providing a short “window of opportunity” for these NK cells to eliminate AML. To address this limitation in the
NK immunotherapy field, we will incorporate a donor-matched RIC HCT, providing an ideal immune-compatible
environment for memory-like NK cells to expand and attack residual AML.
In this proposal, we will 1) test the safety and efficacy of augmenting RIC HCT with same-donor memory-
like NK cell adoptive immunotherapy in a phase 2 clinical trial for patients with AML, 2) define memory-like NK
cell correlates of clinical response, and elucidate key mechanisms important for memory-like NK cell anti-AML
responses. These studies will lead to a new understanding of mechanisms whereby NK cells effectively attack
AML, and whereby AML resists NK cell therapy, and hence strategies to improve memory-like NK cell anti-
AML responses in future clinical trials.
项目总结/摘要
该项目的长期目标是将免疫学领域的新发现转化为早期阶段
白血病患者的免疫治疗临床试验。异基因造血细胞移植(HCT)
高风险或复发性AML的标准治疗,并具有潜在的治愈性。然而,
在老年AML患者中的成功包括1)不能耐受强化调节,2)疾病复发,3)
移植物抗宿主病(GVHD),和4)在许多情况下缺乏合适的供体。一个关键的免疫球员
在介导移植物抗白血病(GvL)效应中也潜在地限制GVHD的是NK细胞。我们
假设NK细胞生物学的新发现可以转化为临床,以提高疗效,
HCT在老年AML患者中的耐受性
最近的临床研究已经报道了来自MHC-半相合供体(haplo-HCT)的HCT,
清髓性预处理方案合并HCT后环磷酰胺可导致临床结局
与来自匹配的无关供体的HCT相当。然而,治疗AML的一个主要障碍是
单倍-HCT患者是大量老年患者,其仅是强度降低的候选者,
预处理(RIC),其导致较低的治疗相关死亡率,但以高得多的发病率为代价
AML复发的风险,以及迄今为止,长期无病生存率很低。为了解决这一领域的重要障碍,
我们将在治疗期间立即用相同供体记忆样NK细胞过继免疫疗法来增加HCT。
在HCT后时期,以增强GvL,同时潜在地改善移植物植入并最小化GVHD。
最近有报道发现,NK细胞在联合细胞因子后表现出“记忆样”特性,
预激活。我们和其他人已经确定,人类记忆样NK细胞在免疫后会产生强烈的反应。
二次刺激,具有多种抗肿瘤特性。我们已经将其转化为细胞疗法,
复发性/难治性(rel/ref)AML患者,并已完成1期研究。然而,这样做的一个缺点
同种异体NK细胞治疗是在2-3周后被接受者的恢复中的免疫系统排斥,
为这些NK细胞消除AML提供了短暂的“机会之窗”。为了解决此限制,
在NK免疫治疗领域,我们将结合供体匹配的RIC HCT,提供理想的免疫相容性
记忆样NK细胞扩增和攻击残留AML的环境。
在这项提案中,我们将1)测试用相同供体记忆增强RIC HCT的安全性和有效性-
如AML患者2期临床试验中的NK细胞过继免疫疗法,2)定义记忆样NK细胞
细胞相关的临床反应,并阐明记忆样NK细胞抗AML的重要机制
应答这些研究将导致对NK细胞有效攻击的机制的新理解
AML,并且由此AML抵抗NK细胞疗法,因此改善记忆样NK细胞抗-NK细胞治疗的策略,
未来临床试验中的AML反应。
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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{{ truncateString('TODD A FEHNIGER', 18)}}的其他基金
TRANSLATING NK CELL BIOLOGY INTO CLINICAL CANCER IMMUNOTHERAPY
将 NK 细胞生物学转化为临床癌症免疫治疗
- 批准号:
9767734 - 财政年份:2017
- 资助金额:
$ 23.88万 - 项目类别:
TRANSLATING NK CELL BIOLOGY INTO CLINICAL CANCER IMMUNOTHERAPY
将 NK 细胞生物学转化为临床癌症免疫治疗
- 批准号:
10017898 - 财政年份:2017
- 资助金额:
$ 23.88万 - 项目类别:
Project 5 - Memory-like NK cell augmented hematopoietic cell transplantation for AML.
项目 5 - 记忆样 NK 细胞增强造血细胞移植治疗 AML。
- 批准号:
10439627 - 财政年份:2013
- 资助金额:
$ 23.88万 - 项目类别:
MICRORNA REGULATION OF NK CELL DEVELOPMENT AND FUNCTION
微小RNA对NK细胞发育和功能的调节
- 批准号:
8583090 - 财政年份:2013
- 资助金额:
$ 23.88万 - 项目类别:
MICRORNA REGULATION OF NK CELL DEVELOPMENT AND FUNCTION
微小RNA对NK细胞发育和功能的调节
- 批准号:
8715686 - 财政年份:2013
- 资助金额:
$ 23.88万 - 项目类别:
MICRORNA REGULATION OF NK CELL DEVELOPMENT AND FUNCTION
微小RNA对NK细胞发育和功能的调节
- 批准号:
8890768 - 财政年份:2013
- 资助金额:
$ 23.88万 - 项目类别:
Project 5 - Memory-like NK cell augmented hematopoietic cell transplantation for AML.
项目 5 - 记忆样 NK 细胞增强造血细胞移植治疗 AML。
- 批准号:
10194404 - 财政年份:2013
- 资助金额:
$ 23.88万 - 项目类别:
MICRORNA REGULATION OF NK CELL DEVELOPMENT AND FUNCTION
微小RNA对NK细胞发育和功能的调节
- 批准号:
9097519 - 财政年份:2013
- 资助金额:
$ 23.88万 - 项目类别:
Molecular Mechanisms of Natural Killer Cell Cytokine-Activation
自然杀伤细胞细胞因子激活的分子机制
- 批准号:
7810611 - 财政年份:2009
- 资助金额:
$ 23.88万 - 项目类别:
Molecular Mechanisms of Natural Killer Cell Cytokine-Activation
自然杀伤细胞细胞因子激活的分子机制
- 批准号:
8244451 - 财政年份:2009
- 资助金额:
$ 23.88万 - 项目类别:
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