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Abstract：
A novel disialoganglioside 2 (GD2)-specific chimeric antigen receptor (CAR)-modified T cell therapy against retinoblastoma (RB) were generated. GD2-CAR consists of a single-chain variable fragment (scFv) derived from a monoclonal antibody, hu3F8, that is linked with the cytoplasmic signaling domains of CD28, 41BB, a CD3ζ, and an inducible caspase 9 death fusion partner. GD2 antigen is highly expressed in Y79RB cell line and in several surgical RB tumor specimens. In vitro co-culture experiments revealed the effective killing of Y79RB cells by GD2-CAR T cells, but not by control CD19-CAR T cells. The killing activities of GD2-CAR T cells were diminished when repeatedly exposed to the tumor, due to an attenuated expression of GD2 antigen on tumor cells and upregulation of inhibitory molecules of the PD1 and PD-L1 axis in the CAR T cells and RB tumor cells respectively. This is the first report to describe the potential of GD2-CAR T cells as a promising therapeutic strategy for RB with the indication of potential benefit of combination therapy with immune checkpoint inhibitors.
摘要：
产生了针对视网膜母细胞瘤（RB）的新型二唾液酸神经节苷脂2（GD2）特异性嵌合抗原受体（CAR）修饰的T细胞疗法。GD2-CAR由来自单克隆抗体的单链可变片段（scFv）组成，hu3F8，与CD28，41BB，CD3ζ，和诱导型caspase9死亡融合伴侣。GD2抗原在Y79RB细胞系和一些手术RB肿瘤标本中高表达。体外共培养实验揭示了GD2-CART细胞对Y79RB细胞的有效杀伤作用,但不是通过控制CD19-CAR-T细胞。GD2-CAR-T细胞的杀伤活性在反复暴露于肿瘤时减弱，由于GD2抗原在肿瘤细胞上的表达减弱，并且分别在CART细胞和RB肿瘤细胞中PD1和PD-L1轴的抑制分子上调。这是第一份描述GD2-CAR-T细胞作为RB有前途的治疗策略的潜力的报告，表明与免疫检查点抑制剂联合治疗的潜在益处。
