PDF(Pubmed)
Abstract：
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.
摘要：
嵌合抗原受体（CAR）T细胞靶向成纤维细胞生长因子受体4（FGFR4），横纹肌肉瘤（RMS）中高表达的表面酪氨酸受体，已经处于临床发展阶段，但是肿瘤异质性和次优激活可能会阻碍它们的效力。在这里，我们报告了FGFR4CAR的共刺激和靶向特性的优化策略。我们用CD28的那些替换CD8铰链和跨膜结构域和4-1BB共刺激结构域。除了侵袭性肿瘤细胞系外，所得CAR在几种RMS异种移植模型中显示出增强的抗肿瘤活性。RMS559。通过寻找RMS核心调节转录因子MYOD1的直接靶标，我们确定了另一种表面蛋白，CD276，作为潜在靶标。双顺反子CAR（BiCisCAR）靶向FGFR4和CD276，含有两个不同的共刺激结构域，与优化的FGFR4特异性CAR和具有相同4-1BB共刺激结构域的其他BiCisCAR相比,具有优异的延长的持久性和增强的抗肿瘤活性。因此，我们的研究为针对RMS中的FGFR4和CD276的CART细胞疗法奠定了原理证明。
