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

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

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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

Immunotherapy for Chronic Myelogenous Leukemia
慢性粒细胞白血病的免疫治疗
  • 批准号:
    7589607
  • 财政年份:
    2004
  • 资助金额:
    $ 63.06万
  • 项目类别:
Immunotherapy for Chronic Myelogenous Leukemia
慢性粒细胞白血病的免疫治疗
  • 批准号:
    8448304
  • 财政年份:
    2004
  • 资助金额:
    $ 63.06万
  • 项目类别:
Immunotherapy for Chronic Myelogenous Leukemia
慢性粒细胞白血病的免疫治疗
  • 批准号:
    8249146
  • 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
  • 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
  • 批准号:
    7025622
  • 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
  • 批准号:
    7174176
  • 财政年份:
    2004
  • 资助金额:
    $ 63.06万
  • 项目类别:
Immunotherapy for Chronic Myelogenous Leukemia
慢性粒细胞白血病的免疫治疗
  • 批准号:
    7802940
  • 财政年份:
    2004
  • 资助金额:
    $ 63.06万
  • 项目类别:
Immunotherapy for Chronic Myelogenous Leukemia
慢性粒细胞白血病的免疫治疗
  • 批准号:
    8088191
  • 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
  • 批准号:
    6858586
  • 财政年份:
    2004
  • 资助金额:
    $ 63.06万
  • 项目类别:
Chaperone rich cell lysates (CRCL)Natural adjuvants and*
富含分子伴侣的细胞裂解物 (CRCL)天然佐剂和*
  • 批准号:
    6770133
  • 财政年份:
    2003
  • 资助金额:
    $ 63.06万
  • 项目类别:

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术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
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流感疫苗类 AS01 合成佐剂系统 SAS 的开发
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