FGFR4-Targeted Chimeric Antigen Receptors Combined with Anti-Myeloid Polypharmacy Effectively Treat Orthotopic...

Area of Science:

• Oncology
• Immunotherapy
• Cancer Biology

Background:

• Rhabdomyosarcoma (RMS) is a common pediatric soft tissue cancer with poor outcomes for relapsed or metastatic disease.
• Current treatments lack novel therapies, and low tumor mutational burden limits efficacy.
• Chimeric antigen receptor (CAR) T-cell therapy presents a potential novel treatment strategy for RMS.

Purpose of the Study:

• To evaluate the feasibility of an FGFR4-targeted CAR T-cell therapy for RMS.
• To overcome challenges posed by the immunosuppressive tumor microenvironment in RMS.
• To develop a combination strategy for enhanced CAR T-cell efficacy in RMS.

Main Methods:

• Developed and refined an FGFR4-targeted CAR using phage display, focusing on membrane-proximal domain binders.
• Utilized an NSG mouse model with orthotopic RH30 RMS tumors to assess CAR T-cell therapy.
• Implemented a multi-drug pharmacologic strategy to inhibit the immunosuppressive myeloid component of the tumor stroma.

Main Results:

• Initial FGFR4 CAR T-cells were ineffective due to the collagen-rich, immunosuppressive myeloid stroma produced by RMS tumors.
• Refined CAR binders targeting the membrane-proximal domain of FGFR4 improved efficacy.
• Combined FGFR4 CAR T-cell therapy with anti-myeloid polypharmacy (targeting CSF1R, IDO1, iNOS, TGFbeta, PDL1, MIF, and myeloid misdifferentiation) led to successful clearance of orthotopic RMS tumors.

Conclusions:

• FGFR4-targeted CAR T-cell therapy can be effective against RMS.
• Reversing the immunosuppressive tumor microenvironment is critical for CAR T-cell success in RMS.
• Combination therapy holds promise for treating RMS, even with low-copy-number targets.