Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma.
Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma.
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双唾液酸神经节苷脂特异性人类自然杀伤细胞可有效对抗耐药神经母细胞瘤。
DOI：
10.1007/s00262-015-1669-5
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Lode,HolgerN
中科院分区：
文献类型：
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作者：
Seidel,Diana;Shibina,Anastasia;Siebert,Nikolai;Wels,WinfriedS;Reynolds,CPatrick;Huebener,Nicole;Lode,HolgerN
双唾液酸神经节苷脂 GD2 是神经母细胞瘤 (NB) 被动免疫治疗的成熟靶抗原。尽管最近使用抗 GD2 抗体 ch14.18 和细胞因子的被动免疫疗法取得了成功，但高风险 NB 的治疗仍然具有挑战性。我们将 GD2 特异性、基于抗体的免疫疗法扩展到 GD2 特异性自然杀伤 (NK) 细胞系 NK-92-scFv(ch14.18)-zeta 的应用。 NK-92-scFv(ch14.18)-zeta 经过基因工程改造，可表达由 ch14.18 生成的 GD2 特异性嵌合抗原受体。在这里，我们表明嵌合受体表达使 NK-92-scFv(ch14.18)-zeta 能够有效裂解 GD2+NB 细胞，也包括部分或多药耐药细胞系。我们的数据表明，嵌合受体对 GD2 的识别是 NK-92-scFv(ch14.18)-zeta 介导的裂解所涉及的主要机制，并且与激活 NK 细胞受体/配体相互作用无关。此外，我们证明 NK-92-scFv(ch14.18)-zeta 能够在耐药 GD2+NB 异种移植小鼠模型中介导显着的体内抗肿瘤反应。 NK-92-scFv(ch14.18)-zeta 是一种 NB 特异性 NK 细胞系，由于其对 GD2+NB 细胞系的高稳定性和活性，具有未来临床开发的潜力。
The disialoganglioside GD2 is a well-established target antigen for passive immunotherapy in neuroblastoma (NB). Despite the recent success of passive immunotherapy with the anti-GD2 antibody ch14.18 and cytokines, treatment of high-risk NB remains challenging. We expanded the approach of GD2-specific, antibody-based immunotherapy to an application of a GD2-specific natural killer (NK) cell line, NK-92-scFv(ch14.18)-zeta. NK-92-scFv(ch14.18)-zeta is genetically engineered to express a GD2-specific chimeric antigen receptor generated from ch14.18. Here, we show that chimeric receptor expression enables NK-92-scFv(ch14.18)-zeta to effectively lyse GD2+NB cells also including partially or multidrug-resistant lines. Our data suggest that recognition of GD2 by the chimeric receptor is the primary mechanism involved in NK-92-scFv(ch14.18)-zeta-mediated lysis and is independent of activating NK cell receptor/ligand interactions. Furthermore, we demonstrate that NK-92-scFv(ch14.18)-zeta is able to mediate a significant anti-tumor response in vivo in a drug-resistant GD2+NB xenograft mouse model. NK-92-scFv(ch14.18)-zeta is an NB-specific NK cell line that has potential for future clinical development due to its high stability and activity toward GD2+NB cell lines.