Genome Engineered Natural Killer Cell Immunotherapy against Human Osteosarcoma

针对人类骨肉瘤的基因组工程自然杀伤细胞免疫疗法

基本信息

  • 批准号:
    10312632
  • 负责人:
  • 金额:
    $ 3.2万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-16 至 2025-08-15
  • 项目状态:
    未结题

项目摘要

Abstract Over the last decade Chimeric Antigen Receptor based T cell therapy (CAR-T) has developed into an effective immunotherapy for some cancers. However, CAR-T cell therapies have several shortcomings and clinical success has primarily been limited to hematological cancers. Challenges of CAR-T cell therapy include tumor immune evasion through loss of target antigen expression by tumor cells and inhibition of CAR-T cell function by tumor expressed inhibitory molecules. Natural killer (NK) cells present an alternative to T cells that could be more effective due to their ability to perform both antigen dependent and independent killing. NK cells have demonstrated antigen specific killing when engineered to express T cell CARs and NK cells also mediate the direct killing of transformed cells with reduced or absent MHC expression. In fact, NK cells carry out antibody dependent cell mediated cytotoxicity (ACDD) of cells that bind antibodies via the NK cell CD16A receptor. Due to the multiple modalities for cancer cell killing, there is an increased interest in NK cells for cancer immunotherapy. As NK cells are not associated with graft versus host disease, neurotoxicity, long-term autoimmunity, nor cytokine release syndrome, they are more suited for use in allogeneic settings than T cells and have significant clinical potential for use as off-the-shelf products. However, previous publications and clinical trials have demonstrated that the use of unmanipulated NK cells to treat cancer is minimally effective, likely due to limited engraftment, little in vivo expansion, and suppression by the tumor microenvironment. NK cells activated and expanded with feeder cells expressing membrane bound interleukin-21 (mbIL-21) have shown promising results clinically with high-risk myeloid malignancies and preclinically in several solid tumor models. Therefore, we hypothesize that activated/expanded NK cells that have be genetically edited can be used to successfully treat osteosarcoma, a disease for which patient outcome has not improved in over thirty years. Our proposed objectives are to evaluate the baseline response of rested- and activated-NK cells against various osteosarcoma cell lines, knockout negative regulators of NK cell function (specifically, c-CBL, IL-1R8, and SMAD3), and implement a specific CAR that optimally activates NK cell antigen-specific killing. Genetically engineered NK cells will be evaluated for enhanced therapeutic efficacy and safety in osteosarcoma models. Our preliminary data strongly supports the hypothesis that NK cell-based cancer immunotherapy can be fully realized using activated, genome engineered NK cells.
摘要 在过去的十年中,基于嵌合抗原受体的T细胞疗法(CAR-T)已经发展成为一种有效的免疫疗法。 对某些癌症的免疫治疗。然而,CAR-T细胞疗法具有几个缺点和临床应用。 成功主要限于血液癌症。CAR-T细胞疗法的挑战包括肿瘤 通过肿瘤细胞失去靶抗原表达和抑制CAR-T细胞功能的免疫逃避 通过肿瘤表达的抑制分子。自然杀伤(NK)细胞是T细胞的替代品, 由于它们能够进行抗原依赖性和非依赖性杀伤,因此更有效。NK细胞具有 当被工程化以表达T细胞汽车时,证明了抗原特异性杀伤,并且NK细胞也介导抗原特异性杀伤。 直接杀死MHC表达减少或缺失的转化细胞。事实上,NK细胞携带抗体, 通过NK细胞CD 16 A受体结合抗体的细胞的依赖性细胞介导的细胞毒性(ACDD)。由于 由于癌症细胞杀伤的多种方式,人们对NK细胞治疗癌症的兴趣越来越大, 免疫疗法由于NK细胞与移植物抗宿主病、神经毒性、长期 自身免疫,也不是细胞因子释放综合征,它们比T细胞更适合用于同种异体环境 并且具有用作现成产品的显著临床潜力。然而,以前的出版物和 临床试验已经证明使用未经操作的NK细胞治疗癌症的效果最低, 这可能是由于有限的植入、很少的体内扩增和肿瘤微环境的抑制。NK 用表达膜结合白细胞介素-21(mbIL-21)的饲养细胞活化和扩增的细胞, 在高危骨髓恶性肿瘤的临床和几种实体瘤的临床前研究中显示出有希望的结果 模型因此,我们假设已经被基因编辑的活化/扩增的NK细胞可以被激活。 用于成功治疗骨肉瘤,这种疾病的患者结局在30多年来没有改善, 年我们提出的目标是评估静息和活化NK细胞对 各种骨肉瘤细胞系,敲除NK细胞功能的负调节因子(具体地,c-CBL,IL-1 R8, 和SMAD 3),并实现最佳激活NK细胞抗原特异性杀伤的特异性CAR。基因 将评估工程化NK细胞在骨肉瘤模型中增强的治疗功效和安全性。 我们的初步数据有力地支持了基于NK细胞的癌症免疫疗法可以被完全抑制的假设。 使用激活的基因组工程NK细胞实现。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Gabrielle Matilde Robbins其他文献

Gabrielle Matilde Robbins的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Gabrielle Matilde Robbins', 18)}}的其他基金

Genome Engineered Natural Killer Cell Immunotherapy against Human Osteosarcoma
针对人类骨肉瘤的基因组工程自然杀伤细胞免疫疗法
  • 批准号:
    10466803
  • 财政年份:
    2021
  • 资助金额:
    $ 3.2万
  • 项目类别:
Genome Engineered Natural Killer Cell Immunotherapy against Human Osteosarcoma
针对人类骨肉瘤的基因组工程自然杀伤细胞免疫疗法
  • 批准号:
    10670762
  • 财政年份:
    2021
  • 资助金额:
    $ 3.2万
  • 项目类别:

相似海外基金

HLA-homozygous iPSC-cardiomyocytE Aggregate manufacturing technoLogies for allogenic cell therapy to the heart (HEAL)
HLA-纯合 iPSC-心肌细胞 用于心脏同种异体细胞治疗 (HEAL) 的聚集体制造技术
  • 批准号:
    10039902
  • 财政年份:
    2022
  • 资助金额:
    $ 3.2万
  • 项目类别:
    EU-Funded
Evaluation of the efficacy of LAT1 inhibitor to tumor stroma and immunity in an allogenic mouse model of colon cancer having abundant stroma.
在具有丰富基质的同种异体结肠癌小鼠模型中评估 LAT1 抑制剂对肿瘤基质和免疫的功效。
  • 批准号:
    21K15925
  • 财政年份:
    2021
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Mechanism of kidney injury associated with graft-versus-host disease after allogenic stem cell transplantation
同种异体干细胞移植后移植物抗宿主病相关肾损伤的机制
  • 批准号:
    21K08410
  • 财政年份:
    2021
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Clarification of the origin and maintenance mechanisms of junctional epithelium and identification of its stem cells using allogenic tooth germ transplantation
阐明交界上皮的起源和维持机制并利用同种异体牙胚移植鉴定其干细胞
  • 批准号:
    20K21672
  • 财政年份:
    2020
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
The study about the allogenic MSCs transplantation to the cardiac disease models.
同种异体间充质干细胞移植至心脏病模型的研究。
  • 批准号:
    18K16395
  • 财政年份:
    2018
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Artificial nerves containing allogenic basal lamellae scaffold and bone marrow derived stem cells
含有同种异体基底板层支架和骨髓干细胞的人工神经
  • 批准号:
    17K10951
  • 财政年份:
    2017
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Role of HSP90-alpha in preserving immunoprivilege of allogenic mesenchymal stem cells in the ischemic heart
HSP90-α 在保护缺血心脏同种异体间充质干细胞免疫特权中的作用
  • 批准号:
    370541
  • 财政年份:
    2017
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Operating Grants
Attempt to Prefabricate Vascularized Allogenic Bone in Recipient -Use of Cultured Bone Marrow Cells-
尝试在受者体内预制血管化的同种异体骨 - 使用培养的骨髓细胞 -
  • 批准号:
    16K10863
  • 财政年份:
    2016
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Allogenic micobiota-reconstitution (AMR) for the treatment of patients with diarhea-predominant irritable bowel syndrome (IBS-D) - the AMIRA trial
同种异体微生物群重建 (AMR) 用于治疗腹泻型肠易激综合征 (IBS-D) 患者 - AMIRA 试验
  • 批准号:
    276706135
  • 财政年份:
    2015
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Clinical Trials
Induction of thyme epithelial cells from iPS cells and application to allogenic transplantation
iPS细胞诱导百里香上皮细胞及其在同种异体移植中的应用
  • 批准号:
    15H04915
  • 财政年份:
    2015
  • 资助金额:
    $ 3.2万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了