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

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for rhabdomyosarcoma (RMS).
• Tumor heterogeneity and suboptimal CAR T-cell activation can limit efficacy against RMS.
• Fibroblast Growth Factor Receptor 4 (FGFR4) is a highly expressed surface receptor in RMS targeted by CAR T-cells.

Purpose of the Study:

• To optimize the co-stimulatory and targeting properties of FGFR4-specific CAR T-cells for enhanced anti-tumor activity in RMS.
• To identify alternative surface targets for RMS CAR T-cell therapy.
• To develop and evaluate bicistronic CARs (BiCisCAR) targeting multiple RMS surface antigens.

Main Methods:

• Modification of CAR T-cell constructs by replacing CD8 hinge/transmembrane and 4-1BB co-stimulatory domains with CD28 domains.
• Identification of CD276 as a novel surface target by investigating MYOD1 downstream targets.
• Construction and in vivo testing of bicistronic CARs (BiCisCAR) targeting both FGFR4 and CD276 in RMS xenograft models.

Main Results:

• Optimized FGFR4 CAR T-cells demonstrated enhanced anti-tumor activity in most RMS xenografts, but not all.
• CD276 was identified as a viable surface target for RMS.
• BiCisCAR targeting both FGFR4 and CD276 exhibited superior and prolonged anti-tumor efficacy compared to single-target CARs.

Conclusions:

• Optimization of CAR T-cell co-stimulatory domains can improve anti-tumor potency.
• Dual targeting of FGFR4 and CD276 represents a promising strategy for enhancing CAR T-cell therapy in RMS.
• This study provides proof-of-principle for a novel BiCisCAR approach for RMS treatment.