Development of FGFR4 targeted Chimeric Antigen Receptors (CARs) for treatment of Rhabdomyosarcoma

C.E. Credits: P.A.C.E. CE Florida CE
Speaker

Abstract

Rhabdomyosarcoma (RMS) is a soft tissue cancer commonly arising in muscle and is the most common soft tissue cancer in children. Patients with metastatic RMS have a poor prognosis that has not improved in decades, highlighting the need for novel therapies. Pediatric tumors, and especially the fusion-gene driven alveolar RMS (aRMS) subset, have low mutational burden, suggesting that checkpoint therapies alone will be insufficient to control tumors. CAR-T cells are genetically engineered T lymphocytes expressing an extracellular binding domain and intracellular T cell signaling domains. Upon engagement of the binding domain to the antigenic target on a tumor cell, T cell-mediated cytotoxicity occurs. CAR specificity requires a molecular target that is tumor specific, expressed on the cell surface, and expressed at high enough levels for CAR-T activation. Previous work identified fibroblast growth factor receptor 4 (FGFR4, CD334) as specifically upregulated in RMS tumors compared to normal tissue, making it a candidate for selective targeting by CAR T cells. A previous CAR designed to target FGFR4 showed in vitro efficacy, and some control of tumor in a metastatic (intravenous) RMS model but failed to control orthotopic (intramuscular) RMS tumors in vivo. We have developed a new generation of FGFR4-binding moieties to be tested as new components of CARs. Our new binders were derived from both human F(ab)- and human VH-only phage display libraries. FGFR4 CARs were screened for surface expression by flow cytometry, cytotoxicity against target and non-target cells, and cytokine production in response to RMS cell lines in vitro. Two F(ab)-based FGFR4-binders were selected for further development against metastatic and intramuscular RMS tumor models in NSG mice. Additionally, we have modeled induced mechanisms of tumor defense in vitro and identified several potential mechanisms of tumor resistance to CAR T therapy which will be exploited to help armor engineered CAR-T cells to control RMS tumors. This data will determine whether our new FGFR4 CARs are sufficient for targeting and eliminating RMS tumors, provide insight into which armoring approaches are best suited to control RMS tumors, and thus develop a potent new therapeutic approach for rhabdomyosarcoma.

Learning Objectives:

1. Explain the disease conditions that make CAR T therapy a good therapeutic option

2. Understand rational CAR design and optimization

3. Describe tumor defense mechanisms and the corresponding CAR T armoring strategies


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