Exercise as an Immune Adjuvant for Gamma Delta T-cell Therapies in Hematologic Malignancies
运动作为血液恶性肿瘤 Gamma Delta T 细胞疗法的免疫佐剂
基本信息
- 批准号:10577605
- 负责人:
- 金额:$ 63.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAdjuvantAdrenergic AgonistsAdrenergic AntagonistsAdrenergic ReceptorAgonistAllogenicAntigen TargetingAntitumor ResponseBiologicalBloodCAR T cell therapyCD19 AntigensCD19 geneCancer PatientCellsCellular immunotherapyClinical TrialsCollecting CellCross-Over TrialsCyclic AMPCyclic AMP ReceptorsDevelopmentDiagnosisExerciseExhibitsFlow CytometryFutureGene Expression ProfileGenesGenetic TranscriptionGoalsGrowthHematologic NeoplasmsHematopoietic NeoplasmsHematopoietic Stem Cell TransplantationHomingHumanImmunologic AdjuvantsIn VitroIn complete remissionInferiorInfusion proceduresInterleukin-15Interleukin-2IsoproterenolK-562K562 CellsKnock-inLigandsLymphocyteMembrane ProteinsMethodsModelingMusNadololNon-Hodgkin&aposs LymphomaOxidative PhosphorylationPathway interactionsPatientsPersonsPhenotypePlacebo ControlPopulation HeterogeneityProliferatingRandomizedReceptor ActivationRecurrent diseaseRefractory DiseaseRelapseRestSignal PathwaySignal TransductionT cell therapyT-Cell ReceptorT-LymphocyteTNFSF10 geneTherapeuticTissuesTreatment Side EffectsTumor ImmunityUp-RegulationVariantVisionZoledronateantagonistantigen testarmbisphosphonatecancer cellchimeric antigen receptorchimeric antigen receptor T cellscytokine release syndromecytotoxiccytotoxicityearly phase clinical trialefficacy testingengineered T cellsexperiencegraft vs host diseasehead-to-head comparisonimprovedin vivoleukemialeukemia relapseleukemia/lymphomamanufacturemetabolic fitnessmigrationmouse modelnovelperipheral bloodpre-clinicalpreclinical studyprogramsprotein expressionreceptorresponsesingle-cell RNA sequencingtranscriptometranscriptomicstumorγδ T cells
项目摘要
SUMMARY: Exercise as an Immune Adjuvant for gd T-cell Therapies in Hematologic Malignancies
gd T-cells are being considered as an alternative to standard CAR ab T-cells for treating leukemic relapse after
hematopoietic stem cell transplantation (HSCT), largely due to their ability to function across MHC barriers
without causing graft-versus-host disease (GvHD)1. gd T-cells can be readily expanded in vitro and in vivo using
zoledronate (ZOL) and have demonstrated anti-tumor activity in preclinical and early phase clinical trials, but
their efficacy against CD19-expressing tumors including acute lymphoblastic leukemia (ALL) and non-Hodgkin’s
lymphoma (NHL) has been modest3. Recently, CD19 CAR gd T-cells were found to have profound effects against
CD19+ tumors in vitro and in xenogeneic mice, albeit inferior to CD19 CAR ab T-cells, although CD19 CAR gd
T-cells were more effective at eliminating CD19 negative escape variants5, 6. As such, if the natural cytotoxicity
of gd T-cells could be enhanced they would become a highly attractive “off the shelf” therapeutic option for ALL
and NHL. Our goal is to improve gd T-cell therapeutics by collecting “superior” gd T-cells that have been mobilized
to peripheral blood by exercise or a synthetic b2-adrenergic receptor (AR) agonist and arming them with a CAR.
We will build on several novel and important observations we have made: (i) a single exercise bout
instantaneously mobilizes gd T-cells bearing a cytotoxic, co-stimulatory and tissue migration phenotype, allowing
their ex vivo manufacture with ZOL+IL-2 to increase by 100-300%4; (ii) exercise expanded gd T-cells have higher
in vitro cytotoxicity against several hematologic tumors4 and are more capable of inhibiting K562 leukemic growth
in xenogeneic mice, particularly when combined with ZOL sensitization; (iii) exercise skews expanded gd T-cells
toward an activated phenotype with heightened NKG2D, TRAIL, DNAM-1 and lowered NKG2A expression, and
blocking these activating receptors, or their ligands on K562 cells, abrogates the exercise effects on gd T-cell
cytotoxicity; and (iv) the mobilization of these superior gd T-cells with exercise is driven by b2-AR activation4. We
hypothesize that exercise will also enhance the quality of CAR gd T-cells by mobilizing gd T-cells with sustained
activation of cytotoxicity, co-stimulation, oxidative phosphorylation, homing and proliferation related genes, and
that this mobilization will be precipitated by increased cAMP signaling. Our aims are: 1) Determine if a single
exercise bout can improve the quality of CAR gd T-cells expanded from healthy donors. 2) Explore the
transcriptomic basis for the enhanced expansion and cytotoxicity of exercise mobilized gd T-cells and expanded
products. 3) Identify the b2-AR signaling pathways responsible for mobilizing gd T-cells with enhanced expansion
and cytotoxicity potential. Our approach involves the use flow cytometry, xenogeneic mouse models, single cell
RNA sequencing, and comparisons with CD19 CAR ab T-cells in human trials involving exercise with b-blockers
and b-agonist infusion models. We expect these aims to identify underpinning mechanisms and pave the way
for a clinical trial whereby exercise/b-agonist mobilized gd T-cells can be collected from donors and cancer
patients to increase the potency of CAR T-cell therapies to treat refractory disease and relapse after HSCT.
总结:运动作为血液肿瘤gd T细胞治疗的免疫佐剂
gd T细胞被认为是标准CAR ab T细胞的替代品,用于治疗白血病复发。
造血干细胞移植(HSCT),主要是由于它们能够跨越MHC屏障发挥作用
而不引起移植物抗宿主病(GvHD)1. gd T细胞可以容易地在体外和体内扩增,
唑来膦酸盐(ZOL),并已在临床前和早期临床试验中显示出抗肿瘤活性,但
它们对表达CD 19的肿瘤的疗效,包括急性淋巴细胞白血病(ALL)和非霍奇金淋巴瘤(NHL)。
淋巴瘤(NHL)一直是温和的3。最近,CD 19 CAR gd T细胞被发现对免疫缺陷病毒具有深远的影响。
体外和异种小鼠中的CD 19+肿瘤,尽管不如CD 19 CAR ab T细胞,但CD 19 CAR gd
T细胞在消除CD 19阴性逃逸变体方面更有效5,6。因此,如果天然细胞毒性
的gd T细胞可以被增强,它们将成为ALL的一种非常有吸引力的“现成”治疗选择。
还有NHL。我们的目标是通过收集动员的“上级”gd T细胞来改善gd T细胞治疗
通过运动或合成的β 2-肾上腺素能受体(AR)激动剂将它们输送到外周血,并用CAR武装它们。
我们将建立在几个新的和重要的意见,我们已经取得:(一)一个单一的演习回合
瞬时动员携带细胞毒性、共刺激和组织迁移表型的gd T细胞,
它们用ZOL+IL-2的离体生产增加100-300%4;(ii)运动扩增的gd T细胞具有更高的
对几种血液肿瘤的体外细胞毒性4,更能抑制K562白血病生长
在异种小鼠中,特别是当与ZOL致敏组合时;(iii)运动使扩增的gd T细胞偏斜
朝向NKG 2D、TRAIL、DNAM-1表达升高和NKG 2A表达降低的活化表型,和
阻断K562细胞上这些活化受体或其配体,可消除运动对gd T细胞的影响。
细胞毒性;和(iv)这些上级gd T细胞的运动动员是由β 2-AR激活驱动的4。我们
假设运动也将通过持续动员gd T细胞来提高CAR gd T细胞的质量,
细胞毒性、共刺激、氧化磷酸化、归巢和增殖相关基因的活化,以及
这种动员将通过增加的cAMP信号传导而加速。我们的目标是:1)确定是否一个单一的
锻炼可以改善从健康供体扩增的CAR gd T细胞的质量。2)探索
运动动员的gd T细胞的增强扩增和细胞毒性的转录组学基础,
产品. 3)鉴定负责动员增强扩增的gd T细胞的b2-AR信号通路
和细胞毒性潜力。我们的方法包括使用流式细胞术,异种小鼠模型,单细胞
RNA测序,以及在涉及使用b受体阻滞剂运动的人体试验中与CD 19 CAR ab T细胞的比较
和β-激动剂输注模型。我们期望这些目标能够确定基础机制并铺平道路
用于临床试验,由此可以从供体和癌症患者收集运动/β-激动剂动员的gd T细胞。
增加CAR T细胞疗法治疗HSCT后难治性疾病和复发的效力。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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EMMANUEL KATSANIS其他文献
EMMANUEL KATSANIS的其他文献
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{{ truncateString('EMMANUEL KATSANIS', 18)}}的其他基金
(CRCL) vaccine for Chronic Myelogenous Leukemia
(CRCL) 慢性粒细胞白血病疫苗
- 批准号:
6718335 - 财政年份:2004
- 资助金额:
$ 63.06万 - 项目类别:
(CRCL) vaccine for Chronic Myelogenous Leukemia
(CRCL) 慢性粒细胞白血病疫苗
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- 资助金额:
$ 63.06万 - 项目类别:
(CRCL) vaccine for Chronic Myelogenous Leukemia
(CRCL) 慢性粒细胞白血病疫苗
- 批准号:
7174176 - 财政年份:2004
- 资助金额:
$ 63.06万 - 项目类别:
(CRCL) vaccine for Chronic Myelogenous Leukemia
(CRCL) 慢性粒细胞白血病疫苗
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6858586 - 财政年份:2004
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- 批准号:
6770133 - 财政年份:2003
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