肿瘤细胞治疗研究
英文原题：CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma.
CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma.
靶向成纤维细胞生长因子受体4（FGFR4）的嵌合抗原受体（CAR）T细胞，FGFR4是横纹肌肉瘤（RMS）中高表达的surface tyrosine receptor，已进入临床开发阶段，但肿瘤异质性和次优激活可能削弱其效力。
靶向横纹肌肉瘤高表达表面受体FGFR4的CAR-T已进入临床开发，但肿瘤异质性和活化不足可能限制疗效。本研究优化FGFR4 CAR的共刺激和靶向性能，将CD8铰链、跨膜区及4-1BB共刺激域替换为CD28结构。优化后的CAR在多种异种移植模型中增强抗肿瘤活性，但对侵袭性RMS559细胞系例外。研究进一步发现MYOD1可能直接靶向的另一表面蛋白CD276。双顺反子CAR同时靶向FGFR4和CD276，并含两个不同共刺激域；相较优化FGFR4 CAR及使用相同4-1BB域的双顺反子CAR，其抗肿瘤活性更强、更持久且细胞功能更佳。研究为横纹肌肉瘤双靶向FGFR4/CD276 CAR-T提供了概念验证。
Chimeric antigen receptor (CAR) T-cells targeting Fibroblast Growth Factor Receptor 4 (FGFR4), a highly expressed surface tyrosine receptor in rhabdomyosarcoma (RMS), are already in the clinical phase of development, but tumour heterogeneity and suboptimal activation might hamper their potency. Here we report an optimization strategy of the co-stimulatory and targeting properties of a FGFR4 CAR. We replace the CD8 hinge and transmembrane domain and the 4-1BB co-stimulatory domain with those of CD28. The resulting CARs display enhanced anti-tumor activity in several RMS xenograft models except for an aggressive tumour cell line, RMS559. By searching for a direct target of the RMS core-regulatory transcription factor MYOD1, we identify another surface protein, CD276, as a potential target. Bicistronic CARs (BiCisCAR) targeting both FGFR4 and CD276, containing two distinct co-stimulatory domains, have superior prolonged persistent and invigorated anti-tumor activities compared to the optimized FGFR4-specific CAR and the other BiCisCAR with the same 4-1BB co-stimulatory domain. Our study thus lays down the proof-of-principle for a CAR T-cell therapy targeting both FGFR4 and CD276 in RMS.
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