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

基本信息

  • 批准号:
    9767734
  • 负责人:
  • 金额:
    $ 59.58万
  • 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:
    2017-08-09 至 2021-07-31
  • 项目状态:
    已结题

项目摘要

The long term goal of this project is to translate novel findings in the field of innate immunity into early phase immunotherapy clinical trials for patients with hematologic malignancies. In this proposal we focus on acute myeloid leukemia (AML), an aggressive cancer of developing myeloid cells that has a poor prognosis, with <30% of patients treated with standard therapy achieving long-term disease-free survival. While allogeneic hematopoietic cell transplantation (HCT) is a standard treatment that is potentially curative for some patients with AML, this therapy is associated with significant morbidity (graft versus host disease and infection) and treatment-related mortality. This limits HCT applicability and overall effectiveness in this disease of older individuals. One promising strategy that preserves the anti-leukemia effector function against AML, without the morbidity and mortality of HCT, is the adoptive transfer of allogeneic lymphocytes. Natural killer (NK) cells are innate lymphoid cells that are specialized to eliminate malignantly transformed target cells. Clinical studies for AML patients using HLA-haploidentical allogeneic HCT have shown that the reactivity of donor NK cells against the patients' leukemia predicts for long-term disease-free survival. Adoptive immunotherapy with enriched allogeneic NK cell products administered to patients with active AML have resulted in complete remissions, although these are achieved in a minority of patients and are of limited duration. We hypothesize that enhancing NK cell recognition of, and effector function against, AML blasts will result in improved clinical outcomes following adoptive NK cell therapy. Recently, paradigm shifting studies have shown that NK cells exhibit immune memory, a property previously attributed only to adaptive T and B lymphocytes. We have established that human NK cells exhibit innate memory following a brief combined stimulation with interleukins (IL)-12, -15, and -18. Preliminary data demonstrates that memory-like NK cells exhibit significantly enhanced AML recognition, functionality, longevity, and proliferative potential compared to naive or control NK cells. Recent preliminary data also shows that administration of allogeneic memory-like NK cells is safe, feasible, and results in clinical responses in AML patients. Thus, we hypothesize that allogeneic memory-like NK cells administered as adoptive immunotherapy for patients with AML will exhibit potent anti-leukemia responses. In this proposal, we will 1) test the safety and efficacy of allogeneic memory-like NK cell adoptive immunotherapy in a first-in-human phase 1/2 clinical trial for patients with relapsed AML, 2) define memory-like NK cell correlates of clinical response, and elucidate key mechanisms important for memory-like NK cell anti-AML responses, and 3) define the importance of NKG2A as a memory-like NK cell checkpoint, and elucidate mechanisms of AML resistance to memory-like NK cell therapy.
该项目的长期目标是将先天免疫领域的新发现转化为早期阶段 恶性血液病患者的免疫治疗临床试验。在本提案中,我们重点关注急性 骨髓性白血病(AML),一种具有不良预后的发育中的骨髓细胞的侵袭性癌症, <30%接受标准治疗的患者实现了长期无病生存。虽然同种异体 造血细胞移植(HCT)是一种标准治疗方法,对某些患者具有潜在的治愈性 对于AML,这种疗法与显著的发病率(移植物抗宿主病和感染)相关, 治疗相关死亡率。这限制了HCT在老年人这种疾病中的适用性和总体有效性。 个体一种有希望的策略是保留针对AML的抗白血病效应子功能,而不需要使用抗白血病药物。 HCT的发病率和死亡率,是同种异体淋巴细胞的过继转移。 自然杀伤(NK)细胞是先天性淋巴细胞,专门消除恶性转化 靶细胞使用HLA-半相合同种异体HCT对AML患者进行的临床研究表明, 供体NK细胞对患者白血病的反应性预测了长期无病生存。养父 向活动性AML患者施用富集的同种异体NK细胞产物的免疫疗法, 导致完全缓解,尽管这些在少数患者中实现, 持续时间我们推测,增强NK细胞对AML原始细胞的识别和效应子功能, 导致过继NK细胞治疗后临床结果改善。 最近,范式转换研究表明,NK细胞表现出免疫记忆,这是一种特性, 以前只归因于适应性T和B淋巴细胞。我们已经确定,人类NK细胞表现出 用白细胞介素(IL)-12、-15和-18短暂联合刺激后的先天记忆。初步数据 证明记忆样NK细胞表现出显著增强的AML识别、功能性、寿命, 和增殖潜力。近期初步数据也显示, 给予同种异体记忆样NK细胞是安全、可行的,并可导致AML的临床应答 患者因此,我们假设同种异体记忆样NK细胞作为过继性免疫治疗, 将表现出有效的抗白血病反应。在本提案中,我们将1)测试安全性, 同种异体记忆样NK细胞过继免疫治疗在首次人体I/II期临床试验中的疗效 对于复发性AML患者,2)定义记忆样NK细胞与临床反应的相关性,并阐明关键 记忆样NK细胞抗AML反应的重要机制,以及3)定义NKG 2A的重要性 作为记忆样NK细胞检查点,并阐明AML对记忆样NK细胞耐药的机制 疗法

项目成果

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TODD A FEHNIGER其他文献

TODD A FEHNIGER的其他文献

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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:
    10017898
  • 财政年份:
    2017
  • 资助金额:
    $ 59.58万
  • 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:
    $ 59.58万
  • 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:
    $ 59.58万
  • 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:
    $ 59.58万
  • 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:
    $ 59.58万
  • 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:
    10931079
  • 财政年份:
    2013
  • 资助金额:
    $ 59.58万
  • 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:
    $ 59.58万
  • 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:
    $ 59.58万
  • 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:
    $ 59.58万
  • 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:
    $ 59.58万
  • 项目类别:

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VLA-4™ 靶向 67Cu-LLP2A 预处理增强基于 T 细胞的过继免疫疗法的疗效
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  • 批准号:
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  • 财政年份:
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