A Novel CAR T-cell Target for Multiple Myeloma Therapy

Recently developed chimeric antigen receptor (CAR) T-cell therapies targeting BCMA have improved clinical response in patients with multiple myeloma (MM); however, patients who have BCMA-deficient disease or who lose BCMA antigens and relapse require additional treatment options. A study recently explored the potential of CAR T-cell therapies that target FcRH5, a cell surface marker expressed on malignant MM cells. Their findings were presented in Nature Communications.

According to the study’s co-contributors, FcRH5-targeted CAR T cells demonstrated “antigen-specific activation, cytokine secretion, and cytotoxicity against MM cells,” in murine xenograft models, including one model with BCMA deficiency. The study suggested “that targeting FcRH5 with CAR T cells may represent a promising therapeutic avenue for MM.”

FcRH5 CAR T cells reportedly showed anti-tumor activity comparable to BCMA CAR T-cell in vitro and murine model results. Authors did note soluble sIRTA2c-type FcRH5 antigens seemed to somehow inhibit the efficacy of FcRH5 CAR T-cell therapies, though they stated they were able to largely avoid the inhibitory effects by increasing the effector-to-target ratio or extending the co-culture time period.

Based on CD138-positive malignant plasma cells from 28 patients with MM, investigators also established that FcRH5 and BCMA surface expression seemed to be independent of each other based on CD138-positive malignant plasma cells from 28 patients with MM. They then developed a FcRH5 and BCMA bispecific CAR T cell that efficiently targeted cells with either or both FcRH5 and BCMA expression and showed increased efficacy compared with monospecific CAR T-cells in vivo.

Ultimately, the authors concluded that their findings “provide a strong rationale for evaluating FcRH5 CAR-T cells in treating MM with low or dim BCMA expression at presentation or alternatively relapsing with downregulation or loss of BCMA following BCMA-targeted immunotherapies.”

Reference

Jiang D, Huang H, Qin H, et al. Chimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma. Nat Commun. 2023;14(1):3642. doi:10.1038/s41467-023-39395-4