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单链可变片段亲和度调整可以优化抗AMLCAR-NK细胞功能.

Ruyan Rahnama1, Monika Kizerwetter2, Huilin Yang3

  • 1Oncology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.

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概括

针对CD123的化学抗原受体 (CAR) -NK细胞表现出强大的抗急性髓性白血病 (AML) 活性. 较低的CAR结合亲和力增强NK细胞对抗原密度的歧视,导致AML的持续抗瘤作用.

关键词:
细胞工程 细胞工程化学抗原受体 - - CAR免疫治疗是一种免疫疗法.自然杀手 - - NK - - 是一种自然杀手.

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科学领域:

  • 免疫学 免疫学 免疫学
  • 细胞疗法细胞疗法
  • 在瘤学瘤学.

背景情况:

  • 自然杀手 (NK) 细胞具有固有的抗癌特性.
  • 化学抗原受体 (CAR) 工程重定向NK细胞活动以抵抗癌症,包括急性髓性白血病 (AML).
  • CAR结合亲和和和表位向对CAR-NK细胞功能的影响需要进一步研究.

研究的目的:

  • 研究不同CAR结合亲缘关系和向性表位对CAR-NK细胞激活的功能影响.
  • 分析CAR-NK细胞细胞分解突触的形成和抗瘤疗效对抗AML.
  • 了解CAR亲和力如何影响不同时间框架和模型中的CAR-NK细胞反应.

主要方法:

  • 生成的NK-92和初级NK细胞表达AML特异性CARs (26292或7G3向CD123) 具有变体亲缘关系.
  • 进行了体外结合,激活和细胞毒性测定.
  • 使用高分辨率成像和老鼠异种移植模型进行体内评估.

主要成果:

  • CARs的表达很高,并且通过抗原特异激活.
  • 高亲和度的CAR-NK细胞显示出快速的AML细胞杀死,而低亲和度的CAR-NK细胞显示出优越的抗原密度歧视和持续的细胞毒性.
  • 低亲和度的CAR-NK细胞在体内表现出增强的扩张.

结论:

  • 具有不同CD123结合亲和度的CAR-NK细胞表达诱导抗原特异性激活和针对AML的细胞毒性.
  • 相关性依赖的功能差异是时间过程和scFv/epitope特定的.
  • 低亲和度CARs可能为持续的抗瘤活性和体内扩张提供优势.