Molecular Characterization of Anti-Tumor Activity Mediated by Extracellular Vesicles Derived from Natural Killer Cells

自然杀伤细胞来源的细胞外囊泡介导的抗肿瘤活性的分子表征

基本信息

  • 批准号:
    10587355
  • 负责人:
  • 金额:
    --
  • 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:
    2023-02-01 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

Multiple myeloma (MM) is the second most common hematological cancer in the U.S and increasing in frequency. Veterans who served in Vietnam where herbicides like Agent Orange were sprayed may have increased risk of developing MM. Early-stage disease is often asymptomatic, so patients are diagnosed late, with bone pain, kidney dysfunction and infections. Although there has been progress in developing new therapies for MM, it remains incurable. Patients initially achieve remission but ultimately relapse. The disease returns more quickly, tumor cells become more resistant to treatment and the patient’s quality of life declines. Natural killer (NK) cells kill MM cells in vitro and in vivo. Clinical trials using NK cell-based immunotherapy are ongoing but not widely available. Several drugs for MM (bortezomib, carfilzomib, lenalidomide) sensitize MM cells to NK-mediated lysis and/or enhance NK killing activity. However, challenges remain. Therefore, new treatments are needed to extend survival and increase durability of remission in relapsed/refractory patients and those ineligible for front-line therapy. My laboratory developed NK3.3, the only normal human NK cell line. It was cloned from peripheral blood NK cells and kills an array of tumor cells. As NK3.3 cells grow in culture, they release small membrane-bound extracellular vesicles (EVs). We demonstrated that purified NK3.3 EVs kill MM cell lines and primary patient samples, without harming normal cells. NK3.3 EVs also kill drug-resistant and cancer stem cells (CSC). There are many advantages to using NK3.3 EVs for cancer treatment. They can be generated in large quantities, are stable, and can be frozen and thawed without loss of function. EVs are resistant to the hypoxic tumor microenvironment and unlike cellular therapy, do not induce a detrimental cytokine storm. NK3.3-derived EVs may provide the advantages of NK cell therapy without the challenges of expanding cells and side effects. The goal of these studies is to establish the feasibility of using NK3.3-derived EVs for MM treatment. We developed a murine xenograft model of minimal residual disease in MM, which approximates a human clinical condition. After intravenous injection of RPM1-8226 MM cells into immunodeficient mice, tumor cells disseminate, infiltrate bones, and induce osteolytic lesions, characteristics of MM. We will test the ability of NK3.3 EVs to prevent MM recurrence after chemotherapy treatment. Aim 1: Characterize NK3.3 EVs and establish best practices for production. We will develop optimal NK3.3 culture conditions for EV production. Proteomic and lipidomic analysis will be performed on EV preparations. NK3.3 EVs will be evaluated for killing MM cell lines and patient samples and for lack of toxicity against healthy bone marrow, peripheral blood lymphocytes and fibroblasts. Aim 2: Identify the mechanism(s) of NK EV-mediated killing. NK EVs induce caspase-mediated apoptosis. However, like NK cells, NK EVs likely kill via multiple mechanisms. We will evaluate caspase- dependent and independent killing pathways in EV-treated tumor cells. We will inhibit killing pathways by gene knockdown and chemical treatment. MM cell lines and primary tumor cells will be used to determine whether drug-resistant and CSC-like MM cells are sensitive to killing by NK3.3 EVs. Aim 3: Test the in vivo efficacy of NK3.3 EVs in preventing/delaying tumor recurrence in a murine model of minimal residual disease in MM. Different concentrations of NK EVs will be administered intravenously. Tumor dissemination will be monitored by bioluminescence imaging; bone lesions by X-ray and CT scanning. Toxicity will be assessed by analysis of body and organ weights and blood chemistry. Normal and tumor-bearing mice will be infused with labeled NK EVs to monitor biodistribution and half-life. These studies are the first step towards developing NK3.3 EVs as a treatment for MM patients who desperately need new options to improve their quality of life and prolong their survival.
多发性骨髓瘤(MM)是美国第二常见的血液癌症, 频率.在越南服役的退伍军人,在那里喷洒了像橙子剂这样的除草剂, 患MM的风险增加。早期疾病通常无症状,因此患者诊断较晚, 有骨痛肾功能障碍和感染虽然在开发新的 MM的治疗,它仍然无法治愈。患者最初达到缓解,但最终复发。疾病 如果肿瘤细胞复发得更快,肿瘤细胞对治疗的抵抗力就会更强,患者的生活质量就会下降。 自然杀伤(NK)细胞在体外和体内杀死MM细胞。使用基于NK细胞的免疫疗法的临床试验 正在进行,但尚未广泛提供。几种MM药物(硼替佐米、卡非佐米、来那度胺)致敏 MM细胞对NK介导的裂解的抑制和/或增强NK杀伤活性。然而,挑战依然存在。因此,新 需要治疗来延长复发/难治性患者的生存期并增加缓解的持久性 以及那些不适合接受一线治疗的人 我的实验室开发了NK 3.3,这是唯一正常的人类NK细胞系。它是从外周血中克隆出来的 NK细胞并杀死一系列肿瘤细胞。当NK 3.3细胞在培养物中生长时,它们释放小的膜结合的 细胞外囊泡(EV)。我们证明了纯化的NK3.3 EV可以杀死MM细胞系和原发性患者, 样本,而不伤害正常细胞。NK3.3 EV还可以杀死耐药细胞和癌症干细胞(CSC)。 使用NK3.3 EV治疗癌症有许多优点。它们可以大量产生 量,是稳定的,可以冷冻和解冻而不丧失功能。电动汽车对缺氧有抵抗力 肿瘤微环境,并且与细胞疗法不同,不会诱导有害的细胞因子风暴。NK3.3-derived EV可以提供NK细胞治疗的优点,而没有扩增细胞和副作用的挑战。 这些研究的目的是确定使用NK 3.3衍生EV治疗MM的可行性。我们 开发了MM中微小残留病的鼠异种移植模型,其近似于人类临床 条件在将RPM 1 -8226 MM细胞静脉注射到免疫缺陷小鼠中后,肿瘤细胞 传播,渗透骨,并诱导溶骨性病变,MM的特征。我们将测试的能力, NK3.3 EV预防化疗后MM复发。 目标1:表征NK3.3 EV并建立最佳生产实践。我们将开发最佳的 用于EV生产的NK3.3培养条件。将对EV进行蛋白质组和脂质组分析 准备工作将评价NK3.3 EV的杀伤MM细胞系和患者样本以及无毒性 针对健康骨髓、外周血淋巴细胞和成纤维细胞。 目的2:鉴定NK EV介导的杀伤的机制。NK EV诱导caspase介导的 凋亡然而,像NK细胞一样,NK EV可能通过多种机制杀死。我们将评估半胱天冬酶- 依赖性和独立的杀伤途径在EV治疗的肿瘤细胞。我们将通过基因抑制杀人途径 拆卸和化学处理。MM细胞系和原代肿瘤细胞将用于确定是否 耐药性和CSC样MM细胞对NK 3.3 EV的杀伤敏感。 目的3:测试NK3.3 EV在预防/延迟小鼠肿瘤复发中的体内功效 将施用不同浓度的NK EV。 静脉注射肿瘤扩散将通过生物发光成像监测;骨病变通过X射线监测, CT扫描。将通过分析体重和器官重量以及血液化学来评估毒性。正常 并且将用标记的NK EV输注荷瘤小鼠以监测生物分布和半衰期。这些 研究是开发NK3.3 EV作为迫切需要治疗的MM患者的第一步。 新的选择,以改善他们的生活质量和延长他们的生存。

项目成果

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JACKI KORNBLUTH其他文献

JACKI KORNBLUTH的其他文献

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{{ truncateString('JACKI KORNBLUTH', 18)}}的其他基金

Development of Natural Killer (NK) Cell Line-Derived Extracellular Vesicles as a New Treatment for Cancer
开发自然杀伤 (NK) 细胞系衍生的细胞外囊泡作为癌症的新治疗方法
  • 批准号:
    10383462
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
NKLAM 分析:与细胞毒性相关的新基因
  • 批准号:
    8413781
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
NKLAM 分析:与细胞毒性相关的新基因
  • 批准号:
    8696768
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
NKLAM: An RBR E3 Ubiquitin Ligase Essential for Regulation of Innate Immunity
NKLAM:一种 RBR E3 泛素连接酶,对于调节先天免疫至关重要
  • 批准号:
    9898218
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
NKLAM 分析:与细胞毒性相关的新基因
  • 批准号:
    8795661
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Analysis of NKLAM: A Novel Gene Associated With Cellular Cytotoxicity
NKLAM 分析:与细胞毒性相关的新基因
  • 批准号:
    8243104
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
PLATELET-ACTIVATING FACTOR AND METASTASIS: CALCIUM-INDEPENDENT PHOSPHOLIPASE
血小板激活因子和转移:钙非依赖性磷脂酶
  • 批准号:
    8361461
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Role of Natural Killer Lytic-Associated Molecule (NKLAM) in Natural Killer Functi
自然杀伤裂解相关分子 (NKLAM) 在自然杀伤功能中的作用
  • 批准号:
    8123617
  • 财政年份:
    2010
  • 资助金额:
    --
  • 项目类别:
NKLAM--A NOVEL GENE REQUIRED FOR NK FUNCTION
NKLAM--NK 功能所需的新型基因
  • 批准号:
    2103280
  • 财政年份:
    1993
  • 资助金额:
    --
  • 项目类别:
NKLAM--A NOVEL GENE REQUIRED FOR NK FUNCTION
NKLAM--NK 功能所需的新型基因
  • 批准号:
    2103282
  • 财政年份:
    1993
  • 资助金额:
    --
  • 项目类别:

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Milk fat globule-EGF factor 8 and hepatocyte apoptosis-induced liver wound healing response
乳脂肪球-EGF因子8与肝细胞凋亡诱导的肝脏创面愈合反应
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