CELL INTELLIGENCE · 肿瘤细胞治疗研究

Children with recurrent/metastatic neuroblastoma (NB) have a dismal survival (<25%). Novel therapies are desperately needed. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed on NB. C021 is a selective oncolytic herpes simplex virus modified to overexpress human interleukin-21 (hIL-21), a cytokine that enhances natural killer (NK) cell cytotoxicity. In the current study, we successfully engineered ex - vivo -expanded NK cells to express a chimeric antigen receptor (CAR) against ROR1 using mRNA electroporation and investigated the efficacy of anti-ROR1-CAR-NK cells combined with C021 in targeting ROR1 + NB. We found that C021-infected NB cells secreted hIL-21 in vitro and in vivo . Compared to the non-cytokine-secreting parental virus C134, C021 significantly enhanced the in vitro cytotoxicity ( p < 0.05) of anti-ROR1-CAR-NK cells with increased interferon (IFN)- ( p < 0.05), granzyme B ( p < 0.05), and perforin ( p < 0.05) secretion against NB cells. Furthermore, the combination of C021 and anti-ROR1-CAR-NK cells significantly extended the survival of human NB xenografted NSG mice compared to controls (mock NK, ROR1-CAR-NK, C134, C021, C134+ROR1-CAR-NK, and C021+mock NK). Our results suggest that cytokine-secreting oncolytic virus in combination with CAR-NK cells is a novel, effective immunotherapeutic approach for high-risk NB.