肿瘤细胞治疗研究
英文原题：Efficiently targeting neuroblastoma with the combination of anti-ROR1 CAR NK cells and N-803 in vitro and in vivo in NB xenografts.
在体内，与单用 anti-ROR1 CAR exPBNK 相比，anti-ROR1 CAR exPBNK 联合 N-803 显著（p < 0.05）提高了人 ROR1⁺ NB 异种移植 NSG 小鼠的生存率。
复发和/或难治性神经母细胞瘤患儿预后很差。神经母细胞瘤细胞表面高表达的孤儿受体酪氨酸激酶ROR1可作为新型免疫治疗靶点。研究评估体外扩增外周血NK细胞所构建的抗ROR1 CAR-exPBNK细胞，并考察与IL-15超激动剂N-803联用的体内外抗肿瘤作用。相较未改造细胞，抗ROR1 CAR-exPBNK对ROR1阳性肿瘤细胞的杀伤增强，N-803可进一步提升细胞毒性，并增强相关细胞中的STAT5磷酸化和Ki67水平。在人ROR1阳性神经母细胞瘤异种移植小鼠中，CAR细胞联合N-803较单用CAR细胞显著延长生存。结果为进一步开发该联合免疫疗法治疗复发/难治性ROR1阳性神经母细胞瘤提供了依据。
The prognosis for children with recurrent and/or refractory neuroblastoma (NB) is dismal. The receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is highly expressed on the surface of NB cells, provides a potential target for novel immunotherapeutics. Anti-ROR1 chimeric antigen receptor engineered ex vivo expanded peripheral blood natural killer (anti-ROR1 CAR exPBNK) cells represent this approach. N-803 is an IL-15 superagonist with enhanced biological activity. In this study, we investigated the in vitro and in vivo anti-tumor effects of anti-ROR1 CAR exPBNK cells with or without N-803 against ROR1 + NB models. Compared to mock exPBNK cells, anti-ROR1 CAR exPBNK cells had significantly enhanced cytotoxicity against ROR1 + NB cells, and N-803 further increased cytotoxicity. High-dimensional analysis revealed that N-803 enhanced Stat5 phosphorylation and Ki67 levels in both exPBNK and anti-ROR1 CAR exPBNK cells with or without NB cells. In vivo, anti-ROR1 CAR exPBNK plus N-803 significantly ( p < 0.05) enhanced survival in human ROR1 + NB xenografted NSG mice compared to anti-ROR1 CAR exPBNK alone. Our results provide the rationale for further development of anti-ROR1 CAR exPBNK cells plus N-803 as a novel combination immunotherapeutic for patients with recurrent and/or refractory ROR1 + NB.
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