BCMA CAR-T cells(Shenzhen Geno-Immune Medical Institute)

B-cell maturation antigen (BCMA) is the lead antigen for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). A challenge is inter- and intra-patient heterogeneity in BCMA expression on MM cells and BCMA downmodulation under therapeutic pressure. Accordingly, there is a desire to augment and sustain BCMA expression on MM cells in patients that receive BCMA-CAR T-cell therapy. We used all-trans retinoic acid (ATRA) to augment BCMA expression on MM cells and to increase the efficacy of BCMA-CAR T cells in pre-clinical models. We show that ATRA treatment leads to an increase in BCMA transcripts by quantitative reverse transcription polymerase chain reaction and an increase in BCMA protein expression by flow cytometry in MM cell lines and primary MM cells. Analyses with super-resolution microscopy confirmed increased BCMA protein expression and revealed an even distribution of non-clustered BCMA molecules on the MM cell membrane after ATRA treatment. The enhanced BCMA expression on MM cells after ATRA treatment led to enhanced cytolysis, cytokine secretion and proliferation of BCMA-CAR T cells in vitro, and increased efficacy of BCMA-CAR T-cell therapy in a murine xenograft model of MM in vivo (NSG/MM.1S). Combination treatment of MM cells with ATRA and the γ- secretase inhibitor crenigacestat further enhanced BCMA expression and the efficacy of BCMA-CAR T-cell therapy in vitro and in vivo. Taken together, the data show that ATRA treatment leads to enhanced BCMA expression on MM cells and consecutively, enhanced reactivity of BCMA-CAR T cells. The data support the clinical evaluation of ATRA in combination with BCMA-CAR T-cell therapy and potentially, other BCMA-directed immunotherapies.

B cell lymphoma can co-occur with multiple myeloma (MM), and the prognosis in this case is usually poor. We propose the combination of CD19-chimeric antigen receptor (CAR) T cells and BCMA-CAR T cells for the treatment of such patients to obtain a superior prognosis.

We present a 50-year-old patient with previous B cell lymphoma and subsequent multiple myeloma (MM).

A diagnosis of B cell lymphoma and MM was made.

The patient was treated with a combination of haploidentical CD19-chimeric antigen receptor (CAR) T cells and BCMA-CAR T cells.

After CAR T cell therapy, the monoclonal plasma cells in the bone marrow and M protein disappeared.

The combination therapy of CD19- and BCMA-CAR T cells is an effective measure to treat patients with concomitant or borderline cases of B cell lymphoma and MM.