Small molecule γ-secretase inhibitors increase BCMA surface expression on myeloma cells, resulting in enhanced CAR-T cell efficacy.
B cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase complex, which reduces ligand density on tumor cells for CAR-T cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR-T cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR-T cell recognition of tumor cells, and potentially limit efficacy of BCMA directed adoptive T cell therapy. We investigated whether blocking BCMA cleavage by small molecule γ-secretase inhibitors (GSIs) could augment BCMA-targeted CAR-T cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR-T cells in vitro. GSI treatment of MM tumor bearing NOD/SCID/γc-/-mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR-T cell therapy. Importantly, short term GSI administration to MM patients markedly increases the percentage of BCMA+tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, an FDA-approved clinical trial (NCT03502577) has been initiated, combining GSI with concurrent BCMA CAR-T cell therapy.