A proliferation-inducing ligand enhances the anti-tumor effect of BCMA CAR T-cell through inhibition of soluble BCMA.

A proliferation-inducing ligand (APRIL), a ligand of B-cell maturation antigen (BCMA), might have an impact on the efficacy of BCMA CAR T-cell in multiple myeloma. Here, we found plasma concentrations of APRIL increased (> 1 nM) during the first month in patients showing responses to BCMA CAR T-cell therapies, and APRIL levels negatively correlated with soluble BCMA (sBCMA) levels. APRIL bound with sBCMA and decreased the detectability of sBCMA in ELISA detection, an effect different from γ-secretase inhibitor. APRIL also bound cell membrane BCMA but with a much lower affinity comparing with sBCMA. sBCMA bound with BCMA CAR T-cell, and decreased the binding and killing of myeloma cells by BCMA CAR T-cells in vitro. APRIL, at concentrations of 2 and 10 nM, inhibited the binding of sBCMA and BCMA CAR T-cell, and increased the binding and killing of myeloma cells by BCMA CAR T-cells. In murine xenotransplant myeloma models, giving APRIL during the first week after infusion of BCMA CAR T-cells increased IFNγ-positive CAR T-cells in the tumor tissues, and enhanced the anti-tumor effect of CAR T-cell. In conclusion, APRIL counteracted the actions of sBCMA in BCMA CAR T-cell-mediated binding and killing of myeloma cells which might contribute to the efficacy of BCMA CAR T-cell therapies.