![]() FGFR4 was found to be upregulated in both FP- and FN-RMS, though the expression of FGFR4 is higher in FP-RMS where expression is driven by the PAX3–FOXO1 fusion protein ( 12, 16, 17). #TEXMACS MEDIUM DRIVER#Previous work identified FGF Receptor 4 (FGFR4, CD334) as being specifically upregulated in both major subtypes of RMS, a driver of metastasis and tumor survival, and aiding in resistance to chemotherapy, making it a promising candidate for targeting by CAR T cells ( 11–15).įGFR4 is a membrane tyrosine kinase expressed during embryonic muscle development and is largely absent in healthy tissues. Nonetheless, some successes have been seen clinically and suggest that T-cell therapy can be adapted for targeting solid tumors ( 6–10). CAR T-cell therapy has been successfully used to treat hematological cancers, but is currently far less effective against solid tumors, likely due to the uniquely immunosuppressive environment of solid tumors. The key to CAR T-cell therapy success is to guide engineered T cells to a molecular target that is tumor-specific, expressed on the cell surface, and expressed at high enough levels for CAR T cells activation ( 5). Upon engagement of the binding domain (often antibody-derived) to the antigenic target on a tumor cell, activation, and degranulation occurs resulting in cell-mediated toxicity-induced death of the tumor cells. The combined treatment of mice with anti-myeloid polypharmacy (targeting CSF1R, IDO1, iNOS, TGFbeta, PDL1, MIF, and myeloid misdifferentiation) allowed FGFR4 CAR T cells to successfully clear orthotopic RMS tumors, demonstrating that RMS tumors, even with very low copy-number targets, can be targeted by CAR T cells upon reversal of an immunosuppressive microenvironment.Ĭhimeric antigen receptors (CAR) T cells are genetically engineered T lymphocytes expressing an extracellular binding domain and intracellular T-cell signaling domains ( 4). Having improved the CAR, we devised a pharmacologic strategy to augment CAR T-cell activity by inhibiting the myeloid component of the T-cell–induced tumor stroma. When scFV-based binders were selected from phage display, CARs targeting FGFR4 were not effective until our screening approach was refined to identify binders to the membrane-proximal domain of FGFR4. This stromal response is not seen in tumor-only xenografts. The first barrier we noted was that RMS tumors produce a collagen-rich stroma, replete with immunosuppressive myeloid cells, when T-cell therapy is initiated. We tested the feasibility of an FGFR4-targeted CAR for treating RMS using an NSG mouse with RH30 orthotopic (intramuscular) tumors. Previous work identified FGF receptor 4 (FGFR4, CD334) as being specifically upregulated in RMS, making it a candidate target for CAR T cells. The current lack of novel therapies and low tumor mutational burden suggest that chimeric antigen receptor (CAR) T-cell therapy could be a promising approach to treating RMS. Treatment outcomes, particularly for relapsed/refractory or metastatic disease, have not improved in decades. Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. ![]()
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