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Multimodal single-cell profiling reveals the enhanced antitumor activity of FGFR4/CD276 BiCisCAR T cells in rhabdomyosarcoma

ABSTRACT: We have generated a clinical grade CAR T targeting FGFR4 with a CD8 hinge and transmembrane domain (HTM) and a 4-1BB co-stimulatory domain (CSD) that is currently being developed for a clinical trial at the NCI. This standard FGFR4-CAR demonstrated potency in low burden RMS disease but has a more modest effect for bulky disease in RMS orthotopic model. Thus, we developed optimized FGFR4-CARs by modification of HTM or CSD to improve its efficacy. However, these modified FGFR4-CARs, even FGFR4.28HTM.28z CAR were unable to eradicate solid tumors in an more aggressive RMS559 model. CAR T cells targeting another cell surface protein CD276, a direct target of the RMS core-regulatory transcription factor MYOD1 is potent and effective, also could not eradicate the tumor. Therefore, we engineered a bicistronic CAR (BiCisCAR) to target both FGFR4 and CD276, with CD28 and 4-1BB CSDs, respectively, which showed remarkable and rapid tumor eradication compared with either single CAR alone. Here, we utilized a multimodal approach including simultaneous protein and transcriptome measurement at single cell level to characterize each FGFR4 or CD276 CAR T-cell infiltrating in RMS orthotopic xenografts. This assay further determined the molecular basis of superior antitumor effect of FGFR4.28HTM.28z-CD276.8HTM.BBz BiCisCAR T cells compared with other CARs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228127 | GEO | 2024/05/23

REPOSITORIES: GEO

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