Tavakoli Shirin, Samareh-Salavati Maryam, Abdolahi Shahrokh, Verdi Javad, Seyhoun Iman, Vousooghi Nasim, Vaezi Mohammad, Ghaderi Afshin, Ghavamzadeh Ardeshir, Barkhordar Maryam, Ahmadvand Mohammad
Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Adv Pharm Bull. 2024 Dec 30;14(4):918-926. doi: 10.34172/apb.43869. Epub 2024 Dec 5.
The activities and functions of natural killer (NK) cells are regulated by a limited repertoire of activating and inhibitory receptors. Thus, we provided a study of inhibition of the NKG2A using monoclonal antibodies (mAbs), and as a primary endpoint, we evaluated whether it can be translated to enhance adoptive NK cell immunotherapy, as the secondary endpoint, we investigated safety and feasibility.
In this study, we investigated the safety of anti-NKG2A-pretreated NK cells in improving ADCC function to manage hepatocellular carcinoma (HCC). After a conditioning regimen, we initiated a pilot study of expanded donor haploidentical NK cell infusion. Patients received a fludarabine/cyclophosphamide conditioning followed by adoptive immunotherapy with IL2-activated haploidentical NK cells. Anti-NKG2A pretreated NK cells were infused on days 0,+5, and+10 post-conditioning regimens at a dose of 7×10 cells (n=3). The median follow-up was 4 months for all patients.
Although all patients were alive at the last follow-up, two of them showed progressive disease and an increase in tumor size. In addition, all patients showed a relative decrease in alpha-fetoprotein (AFP) expression levels after one month.
This study demonstrated the safety and feasibility of infusing high doses of ex vivo expanded NK cells after conditioning with transient side effects.
自然杀伤（NK）细胞的活性和功能由有限的一组激活和抑制受体调节。因此，我们开展了一项使用单克隆抗体（mAb）抑制NKG2A的研究，作为主要终点，我们评估了其是否可转化用于增强过继性NK细胞免疫治疗，作为次要终点，我们研究了安全性和可行性。
在本研究中，我们研究了抗NKG2A预处理的NK细胞在改善抗体依赖性细胞介导的细胞毒性（ADCC）功能以治疗肝细胞癌（HCC）方面的安全性。在进行预处理方案后，我们启动了一项扩大的供体单倍体相合NK细胞输注的试点研究。患者接受氟达拉滨/环磷酰胺预处理，随后用白细胞介素2激活的单倍体相合NK细胞进行过继免疫治疗。抗NKG2A预处理的NK细胞在预处理方案后的第0、+5和+10天以7×10⁷个细胞的剂量输注（n = 3）。所有患者的中位随访时间为4个月。
尽管在最后一次随访时所有患者均存活，但其中两名患者出现疾病进展且肿瘤大小增加。此外，所有患者在1个月后甲胎蛋白（AFP）表达水平均出现相对下降。
本研究证明了在有短暂副作用的预处理后输注高剂量体外扩增NK细胞的安全性和可行性。
