Chimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma

Abstract

BCMA-targeting chimeric antigen receptor (CAR) T cell therapy demonstrates impressive clinical response in multiple myeloma (MM). However, some patients with BCMA-deficient tumours cannot benefit from this therapy, and others can experience BCMA antigen loss leading to relapse, thus necessitating the identification of additional CAR-T targets. Here, we show that FcRH5 is expressed on multiple myeloma cells and can be targeted with CAR-T cells. FcRH5 CAR-T cells elicited antigen-specific activation, cytokine secretion and cytotoxicity against MM cells. Moreover, FcRH5 CAR-T cells exhibited robust tumoricidal efficacy in murine xenograft models, including one deficient in BCMA expression. We also show that different forms of soluble FcRH5 can interfere with the efficacy of FcRH5 CAR-T cells. Lastly, FcRH5/BCMA-bispecific CAR-T cells efficiently recognized MM cells expressing FcRH5 and/or BCMA and displayed improved efficacy, compared with mono-specific CAR-T cells in vivo. These findings suggest that targeting FcRH5 with CAR-T cells may represent a promising therapeutic avenue for MM.

CAR-T Therapy in Multiple Myeloma: Looking Beyond

“…Therefore, to increase durability and effectiveness of the CAR-T, the product was engineered to include a motif that secreted IL-15. This modified product enhanced anti-MM activity due to its increased durability and provided the CAR-T with stemness-like characteristics [46]. Currently, a phase I/II trial is undergoing evaluation of the efficacy of anti-FcRL5 CAR-T [47].…”

Current Novel Targeted Therapeutic Strategies in Multiple Myeloma

“…FcRH5 CAR T cells have been shown to exhibit robust tumoricidal efficacy both in vitro and in murine xenograft models, including in BCMA-deficient cells [ 70 ]. Furthermore, FcRH5/BCMA tandem CAR T cells, or CAR T cells with dual anti-FcRH5 scFv and anti-BCMA scFv connected to a single stalk, have been shown to display improved efficacy compared with monospecific CAR T cells in murine xenograft models [ 70 ].…”