产生非性抗病毒中心记忆CD8人体维托T细胞用于细胞治疗
Esther Bachar-Lustig1, Assaf Lask2, Yaki Eidelstein2
1Department of Hematopoietic Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, Texas.
Transplantation and cellular therapy
|October 27, 2023
概括
这项研究开发了一种新的方法来产生具有否决活性的CD8 T细胞,显著减少全活性T细胞克隆. 这些细胞在临床试验中增强了骨髓移植,同时最大限度地降低了移植与宿主疾病的风险.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞疗法细胞疗法
- 移植免疫学 移植免疫学
背景情况:
- 以前在小鼠身上进行的研究表明,CD8 T细胞具有否决活性,通过抑制移植对宿主反应来增强骨髓异位移植.
- 产生CD8否决T细胞的策略包括细胞因子剥夺和扩张IL-15,或使用具有特定抗原的记忆T细胞.
- 降低移植对宿主疾病 (GVHD) 风险对于全源造血干细胞移植 (HSCT) 至关重要.
研究的目的:
- 测试在特定的细胞因子条件下对病毒抗原激活的人类CD8记忆T细胞是否会在保留否决功能的同时失去全活性.
- 建立一种用于产生临床级CD8否决细胞的方法,用于T细胞贫的平分异性HSCT.
主要方法:
- 从病毒阳性捐献者的外周血液中提取的记忆CD8T细胞的丰富.
- 单细胞的分离和分化成成熟的树突细胞 (mDC).
- 脉冲mDCs与病毒 (CMV,EBV,腺病毒,BK病毒) 并与CD8 T细胞共同培养在IL-21的存在下,其次是IL-15和IL-7.
- 使用限制稀释分析评估性活性和否决活性.
- 使用良好制造实践 (GMP) 试剂生成细胞用于临床试验.
主要成果:
- 建立了一种可扩展的方法,在12天内产生具有中央记忆表型 (>97%CD3+CD8+,84%CM) 的同质CD8T细胞.
- 这些细胞在体外表现出显著的阻断活性,并且表现出全活性>3-log耗尽.
- 临床验证显示,在12/13个实验中,从单个白血病化中成功生成了>1x10^10个细胞.
- 证实了抗病毒活性,平均38.8%的细胞在刺激时对INF-γ和TNF-α呈阳性.
结论:
- 一种新的方法有效地从抗病毒CD8否决细胞制剂中消耗了全活性T细胞克隆.
- 这些由GMP生成的CD8中央记忆否决细胞适合在非骨髓可塑性T细胞枯竭的单双同性HSCT中临床应用.
- 需要进行进一步的研究,以探索这些细胞在全基接受者中用于现成CAR T细胞治疗的潜力.
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