RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
单倍体相合 mbIL-21 体外扩增 NK 细胞治疗多次复发/难治性急性髓系白血病的 I 期试验结果
英文原题：Results of a phase I trial with Haploidentical mbIL-21 ex vivo expanded NK cells for patients with multiply relapsed and refractory AML.
查看英文原题
Results of a phase I trial with Haploidentical mbIL-21 ex vivo expanded NK cells for patients with multiply relapsed and refractory AML.
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中文摘要
自然杀伤（NK）细胞具有强大的抗肿瘤作用，但其对复发急性髓系白血病（AML）患者是否有效仍不清楚。在一项I期临床试验中，我们治疗了12例难治性AML患者（中位年龄60岁，中位既往治疗线数5线，中位骨髓原始细胞计数47%），方案为氟达拉滨/阿糖胞苷后输注6次NK细胞，这些NK细胞来自单倍体相合供者，使用表达膜结合IL21和4-1BBL的K562饲养细胞扩增。患者接受的剂量为10^6-10^7/kg/次。未观察到毒性或移植物抗宿主病（GVHD），未达到MTD。7例患者（58.3%）获得缓解，达到完全缓解（CR），伴或不伴血细胞计数恢复。达到最佳缓解的中位时间为48天。5例缓解患者接受了来自同一供者的单倍体相合移植。中位随访52个月后，整个队列的1年总生存期（OS）率为41.7%，达到CR/CRi缓解的患者更优（57.14%），缓解并接受移植的患者为60%。在患者血液中检测到供者来源NK细胞的持续存在和扩增，血清IFN水平与NK细胞输注同步升高。较高计数的功能性抑制性KIR与达到CR/CRi的更高可能性相关。
总之，我们观察到体外扩增NK细胞输注对难治性AML患者具有显著疗效，且无不良反应。
展开英文摘要原文
Natural killer (NK)-cells have potent anti-tumor effects, yet it remains unclear if they are effective for patients with relapsed acute myeloid leukemia (AML). In a phase I clinical trial, we treated 12 patients (median age 60 years) with refractory AML (median 5 lines of prior therapy, median bone marrow blast count of 47%) with fludarabine/cytarabine followed by 6 infusions of NK-cells expanded from haploidentical donors using K562 feeder cells expressing membrane-bound IL21 and 4-1BBL. Patients received 10 6 -10 7 /kg/dose. No toxicity or graft-versus-host disease (GVHD) was observed and MTD was not reached. Seven patients (58.
3%) responded and achieved a complete remission (CR) with/without count recovery. Median time to best response was 48 days. Five responding patients proceeded to a haploidentical transplant from the same donor. After a median follow-up of 52 months, 1-year overall survival (OS) for the entire group was 41. 7%, better for patients who responded with CR/CRi (57.
14%), and for patients who responded and underwent transplantation (60%). Persistence and expansion of donor-derived NK-cells were identified in patients' blood, and serum IFN levels rose concurrently with NK cell infusions. A higher count-functional inhibitory KIR was associated with higher likelihood of achieving CR/CRi.
In conclusion, we observed a significant response to ex vivo expanded NK-cell administration in refractory AML patients without adverse effects.
论文信息
- 作者
- Ciurea SO、Kongtim P、Srour S、Chen J、Soebbing D、Shpall E、Rezvani K、Nakkula R
- 第一作者单位
- Hematopoietic Stem Cell Transplant and Cellular Therapy Program, Division of Hematology/Oncology, The University of California, Orange, California, USA.United States
- 通讯作者单位
- The Abigail Wexner Research Institute, Columbus, Ohio, USA.United States
- 文献类型
- I 期临床试验 · 非美国政府资助研究
- 期刊
- American journal of hematology2024 May
- 原文标识
- PubMed 38444268 · DOI 10.1002/ajh.27281
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