Tumor-specific CAR-NK cells for adoptive cancer immunotherapy
用于过继性癌症免疫治疗的肿瘤特异性 CAR-NK 细胞
基本信息
- 批准号:350733817
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2017
- 资助国家:德国
- 起止时间:2016-12-31 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Natural killer (NK) cells hold promise for adoptive cancer immunotherapy. Similar to T cells, the antitumor activity of NK cells can be enhanced by expression of chimeric antigen receptors (CARs) that facilitate selective recognition and killing of malignant cells. Thereby, characteristics unique to NK cells such as their endogenous natural cytotoxicity complementing CAR-mediated antitumor activity, and the low risk of graft versus host disease upon application of donor-derived cells favor the use of NK cells as CAR-engineered effectors. Nevertheless, challenges such as the limited expansion potential of NK cells and reduced effectiveness of CAR gene transfer are slowing clinical development of CAR-engineered primary NK cells. With the proposed project, we aim to investigate directed ex vivo differentiation of hematopoietic stem cells (HSC) as a strategy for the generation of fully functional NK cells, which will be further expanded using specific cytokine cocktails and gene-modified feeder cells to reliably yield high effector cell numbers. This approach will then be employed to generate CAR-engineered NK cells with enhanced antitumor activity, based on lentiviral CAR gene transfer into HSCs followed by ex vivo differentiation into CAR-NK cells. Thereby, a CAR specific for the tumor-associated surface antigen ErbB2 (HER2) will be employed as a clinically relevant model, with CAR expression restricted to the NK cell lineage through the use of an NK-specific promoter. The resulting ex vivo generated NK and CAR-NK cells will be phenotypically and functionally characterized, and their antitumor activity will be tested against cancer cells in vitro and human tumor xenografts in immunodeficient mice in vivo. Subsequently, the principles established during ex vivo differentiation of CAR-NK cells will be applied for in vivo CAR-NK cell differentiation in humanized mouse model systems. Transplantation of HSCs carrying a CAR sequence expressed in NK cells in a lineage-specific manner may facilitate continuous in vivo repopulation with polyclonal CAR-NK cells and allow durable disease control. We expect these studies to establish CAR gene transduced HSCs as a useful source for the generation of tumor-specific CAR-NK cells in therapeutically relevant numbers, which could serve as a promising alternative to currently applied CAR-T cells for the development of effective cancer immunotherapies.
自然杀伤(NK)细胞有望用于过继癌症免疫治疗。与T细胞类似,NK细胞的抗肿瘤活性可以通过表达嵌合抗原受体(CARS)来增强,从而促进对恶性细胞的选择性识别和杀伤。因此,NK细胞特有的特性,如其内源性的天然细胞毒性补充CAR介导的抗肿瘤活性,以及应用供体来源的细胞时移植物抗宿主病的低风险,有利于使用NK细胞作为CAR工程的效应器。然而,诸如NK细胞扩增潜力有限和CAR基因转移有效性降低等挑战正在减缓CAR工程原代NK细胞的临床发展。在这项拟议的项目中,我们的目标是研究造血干细胞(HSC)的体外定向分化作为一种产生全功能NK细胞的策略,这种细胞将使用特定的细胞因子鸡尾酒和基因修饰的饲养细胞进一步扩增,以可靠地产生高效应细胞数量。这种方法将被用来产生具有增强的抗肿瘤活性的CAR工程的NK细胞,基于慢病毒CAR基因转移到HSCs,然后在体外分化为CAR-NK细胞。因此,针对肿瘤相关表面抗原ErbB2(HER2)的CAR将被用作临床相关模型,通过使用NK特异性启动子,CAR的表达仅限于NK细胞谱系。由此产生的体外产生的NK和CAR-NK细胞将进行表型和功能鉴定,并将在体外测试它们对癌细胞的抗肿瘤活性,并在体内对免疫缺陷小鼠的人肿瘤移植瘤进行测试。随后,在体外分化CAR-NK细胞过程中建立的原则将被应用于人源化小鼠模型系统中CAR-NK细胞的体内分化。以谱系特异的方式移植携带在NK细胞中表达的CAR序列的HSCs,可以促进多克隆CAR-NK细胞在体内持续的再繁殖,并允许持久的疾病控制。我们期望这些研究建立CAR基因转导的HSCs作为一种有用的来源,以产生与治疗相关的数量的肿瘤特异性CAR-NK细胞,这可能成为目前应用的CAR-T细胞的一种有前途的替代方案,用于开发有效的癌症免疫疗法。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Directed Differentiation of Mobilized Hematopoietic Stem and Progenitor Cells into Functional NK Cells with Enhanced Antitumor Activity
- DOI:10.3390/cells9040811
- 发表时间:2020-04-01
- 期刊:
- 影响因子:6
- 作者:Oberoi, Pranav;Kamenjarin, Kathrina;Wels, Winfried S.
- 通讯作者:Wels, Winfried S.
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Professor Dr. Winfried Wels其他文献
Professor Dr. Winfried Wels的其他文献
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{{ truncateString('Professor Dr. Winfried Wels', 18)}}的其他基金
Modulation of the tumor microenvironment by CAR-engineered NK cells
CAR 工程 NK 细胞调节肿瘤微环境
- 批准号:
413727587 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Research Grants
Generierung eines genetischen Mausmodells zur Analyse der FoxP3-abhängigen Regulation der ErbB2/HER2-Expression während der Brustdrüsenentwicklung und der Tumorgenese des Mammakarzinoms
建立遗传小鼠模型来分析乳腺发育和乳腺癌肿瘤发生过程中 ErbB2/HER2 表达的 FoxP3 依赖性调节
- 批准号:
87549419 - 财政年份:2008
- 资助金额:
-- - 项目类别:
Research Grants
Effector molecules of the apoptosis-inducing signaling cascade as active components in cytotoxic antibody fusion proteins for cancer therapy
细胞凋亡诱导信号级联的效应分子作为癌症治疗细胞毒性抗体融合蛋白的活性成分
- 批准号:
46199767 - 财政年份:2007
- 资助金额:
-- - 项目类别:
Research Grants
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