肿瘤细胞治疗研究
英文原题：CAR T-cell-mediated delivery of bispecific innate immune cell engagers for neuroblastoma.
需要新的嵌合抗原受体（CAR）T细胞方法来提高实体瘤的治疗效果。
需要新型嵌合抗原受体（CAR）T 细胞方法以提高实体瘤的治疗疗效。高危神经母细胞瘤是一种侵袭性儿童实体瘤，表达细胞表面 GPC2 和 GD2，其肿瘤微环境被表达 CD16a 的先天免疫细胞浸润。在这里，我们改造 T 细胞以表达靶向 GPC2 的 CAR，并同时分泌同时靶向 GD2 和 CD16a 的双特异性先天免疫细胞衔接器（BiCE）。体外，GPC2.CAR-GD2.BiCE T 细胞诱导 GPC2 依赖性细胞毒性，并分泌 GD2.BiCE，促进 GD2 依赖性的抗肿瘤先天免疫激活。体内，GPC2.CAR-GD2.BiCE T 细胞局部递送 GD2.BiCE，并增加 NK 细胞在肿瘤内的滞留。在携带神经母细胞瘤患者来源异种移植瘤并用表达人 CD16a 的免疫细胞重建的小鼠中，GD2.BiCE 增强 GPC2.CAR 的抗肿瘤疗效。对于抗原逃逸限制 CAR 疗效的肿瘤组织学类型，应考虑 CAR.BiCE 策略，尤其是像神经母细胞瘤这样被先天免疫细胞浸润的实体瘤。
Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.
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