嵌合抗原受体(CAR)-NK细胞的最新进展在临床试验中以最小的毒性治疗CD19阳性淋巴肿瘤[包括移植物抗宿主病(GvHD)和细胞因子释放综合征(CRS)。然而,CAR-NK细胞在对抗病毒感染中的应用尚未得到充分探索.先前的研究表明,表达S309单链片段可变(scFv)的CAR-NK细胞,以下S309-CAR-NK细胞,可以与SARS-CoV-2野生型假病毒(PV)结合,并在体外有效杀死表达野生型刺突蛋白的细胞。在这项研究中,我们进一步证明了S309-CAR-NK细胞可以结合不同的SARS-CoV-2变体,包括B.1.617.2(Delta),B.1.621(Mu),和体外B.1.1.529(Omicron)变体。我们还表明,S309-CAR-NK细胞降低了表达人血管紧张素转换酶2(hACE2)受体的NOD/SCIDγ(NSG)小鼠的病毒载量,这些小鼠受到SARS-CoV-2野生型(USA/WA1/2020)的攻击。我们的研究表明,S309-CAR-NK细胞可能用于抑制SARS-CoV-2感染,并可能用于治疗对目前可用的其他疗法无反应的COVID-19患者。
目的:嵌合抗原受体(CAR)-NK细胞可以成为治疗各种疾病的“现成”产品,包括癌症,感染,和自身免疫性疾病。在这项研究中,我们改造自然杀伤(NK)细胞表达S309单链片段可变(scFv),靶向SARS-CoV-2的刺突蛋白,以下称为S309-CAR-NK细胞。我们的研究表明,S309-CAR-NK细胞对不同的SARS-CoV-2变体有效,包括B.1.617.2(Delta),B.1.621(Mu),和B.1.1.529(Omicron)变体。S309-CAR-NK细胞可以(i)直接结合SARS-CoV-2假型病毒(PV),(ii)与表达人血管紧张素转换酶2(hACE2)受体的293T细胞(293T-hACE2细胞)竞争性结合SARS-CoV-2PV,(iii)特异性靶向并裂解表达刺突蛋白的A549细胞,和(iv)显著降低表达hACE2的NOD/SCIDγ(NSG)小鼠(hACE2-NSG小鼠)的肺中SARS-CoV-2野生型(菌株USA/WA1/2020)的病毒载量。总之,本研究表明,S309-CAR-NK免疫疗法可作为COVID-19患者的替代疗法.
Recent progress on chimeric antigen receptor (CAR)-NK cells has shown promising results in treating CD19-positive lymphoid tumors with minimal toxicities [including graft versus host disease (GvHD) and cytokine release syndrome (CRS) in clinical trials. Nevertheless, the use of CAR-NK cells in combating viral infections has not yet been fully explored. Previous studies have shown that CAR-NK cells expressing S309 single-chain fragment variable (scFv), hereinafter S309-CAR-NK cells, can bind to SARS-CoV-2 wildtype pseudotyped virus (PV) and effectively kill cells expressing wild-type spike protein in vitro. In this study, we further demonstrate that the S309-CAR-NK cells can bind to different SARS-CoV-2 variants, including the B.1.617.2 (Delta), B.1.621 (Mu), and B.1.1.529 (Omicron) variants in vitro. We also show that S309-CAR-NK cells reduce virus loads in the NOD/SCID gamma (NSG) mice expressing the human angiotensin-converting enzyme 2 (hACE2) receptor challenged with SARS-CoV-2 wild-type (strain USA/WA1/2020). Our study demonstrates the potential use of S309-CAR-NK cells for inhibiting infection by SARS-CoV-2 and for the potential treatment of COVID-19 patients unresponsive to otherwise currently available therapeutics.
OBJECTIVE: Chimeric antigen receptor (CAR)-NK cells can be \"off-the-shelf\" products that treat various diseases, including cancer, infections, and autoimmune diseases. In this study, we engineered natural killer (NK) cells to express S309 single-chain fragment variable (scFv), to target the Spike protein of SARS-CoV-2, hereinafter S309-CAR-NK cells. Our study shows that S309-CAR-NK cells are effective against different SARS-CoV-2 variants, including the B.1.617.2 (Delta), B.1.621 (Mu), and B.1.1.529 (Omicron) variants. The S309-CAR-NK cells can (i) directly bind to SARS-CoV-2 pseudotyped virus (PV), (ii) competitively bind to SARS-CoV-2 PV with 293T cells expressing the human angiotensin-converting enzyme 2 (hACE2) receptor (293T-hACE2 cells), (iii) specifically target and lyse A549 cells expressing the spike protein, and (iv) significantly reduce the viral loads of SARS-CoV-2 wild-type (strain USA/WA1/2020) in the lungs of NOD/SCID gamma (NSG) mice expressing hACE2 (hACE2-NSG mice). Altogether, the current study demonstrates the potential use of S309-CAR-NK immunotherapy as an alternative treatment for COVID-19 patients.