Boosting CAR T-Cell Efficacy by Blocking Proteasomal Degradation of Membrane Antigens

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Authors	RIEGER Leonie IRLINGER Kilian FÜCHSL Franziska TIETJE Marlene PURCAREA Anna BARBIAN Nicolas Mathis FABER Melanie VOGELSANG Carolin PFEUFFER Lisa STOTZ Sonja KARPIUK Oleksandra SCHULZE Tobias AUGSBURGER Abirami GLAISNER Nadine KONETZKI Verena FRIEDEL Sabrina BEŠŠE Andrej BEŠŠE Lenka DRIESSEN Christoph BUCHNER Maike SCHWAMBORN Kristina STEIGER Katja GIANSANTI Piero THEURICH Sebastian WALDSCHMIDT Johannes M KORTÜM Klaus Martin HUDECEK Michael EINSELE Hermann HÖGNER Marion KUSTER Bernhard AN
Year of publication	2025
Type	Article in Periodical
Magazine / Source	Blood
MU Faculty or unit	Faculty of Medicine
Citation
web	https://ashpublications.org/blood/article/doi/10.1182/blood.2024027616/546138/Boosting-CAR-T-Cell-Efficacy-by-Blocking
Doi	https://doi.org/10.1182/blood.2024027616
Attached files	Boosting_CAR_T-Cell_Efficacy_by_Blocking_Proteasomal_Degradation_of_Membrane_Antigens.pdf
Description	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 (PI). 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, treatment of ten patients with CFZ under the compassionate use CarCAR protocol - after relapse following BCMA CAR T cell therapy - 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 following BCMA CAR T 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.
Related projects:	National institute for cancer research