Boosting CAR T-cell efficacy by blocking proteasomal degradation of membrane antigens

Chimeric antigen receptor (CAR) T cells exhibit high response rates in B-cell malignancies, but most patients eventually relapse. A key mechanism of treatment failure is the loss or downregulation of tumor antigen expression, yet strategies to modulate cell surface levels of CAR T-cell targets remain largely unexplored. Here, we identify B-cell maturation antigen (BCMA), a central CAR T-cell target in multiple myeloma (MM), as a highly short-lived protein that undergoes K48-linked polyubiquitylation at the plasma membrane, leading to its p97-dependent degradation via the ubiquitin-proteasome system (UPS). This previously unprecedented mechanism of plasma membrane protein regulation enables significant enhancement of BCMA expression via proteasome inhibitors (PIs). The clinically approved PI carfilzomib (CFZ) significantly enhances the efficacy of BCMA-directed CAR T cells against both PI-sensitive and -refractory MM cells in vitro and in vivo. Notably, CFZ treatment of 10 patients with BMCA CAR T-cell therapy relapse, under the CFZ after BCMA CAR T-cell (CarCAR) protocol, resulted in increased BCMA expression in all patients. However, clinical responses were observed only in those with residual and/or expanding CAR T cells, suggesting restored CAR T-cell function. These findings provide a rationale for the use of CFZ treatment in relapsed or refractory MM after BCMA CAR T-cell therapy, advocate for future trials combining CFZ with BCMA CAR T cells, and provide a framework for exploring UPS-dependent degradation of other immunotherapy antigens.