CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma

Meijie Tian, Jun S. Wei, Adam Tai-Chi Cheuk, David Milewski, Zhongmei Zhang, Yong Yean Kim, Hsien-Chao Chou, Can Liu, Sherif Badr, Eleanor G. Pope, Abdelrahman Rahmy, Jerry T. Wu, Michael C. Kelly, Xinyu Wen and Javed Khan ()
Additional contact information
Meijie Tian: National Institutes of Health
Jun S. Wei: National Institutes of Health
Adam Tai-Chi Cheuk: National Institutes of Health
David Milewski: National Institutes of Health
Zhongmei Zhang: National Institutes of Health
Yong Yean Kim: National Institutes of Health
Hsien-Chao Chou: National Institutes of Health
Can Liu: NIH
Sherif Badr: National Institutes of Health
Eleanor G. Pope: National Institutes of Health
Abdelrahman Rahmy: National Institutes of Health
Jerry T. Wu: National Institutes of Health
Michael C. Kelly: National Institutes of Health
Xinyu Wen: National Institutes of Health
Javed Khan: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50251-x

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