Boosting CAR T-cell efficacy by blocking proteasomal degradation of membrane antigens
Abstract
Abstract 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.
Article Details
Authors (33)
Leonie Rieger
Kilian Irlinger
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Franziska Füchsl
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Marlene Tietje
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Anna Purcarea
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Nicolas Barbian
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Melanie Faber
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Carolin Vogelsang
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Lisa Pfeuffer
Sonja Stotz
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Oleksandra Karpiuk
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Tobias Schulze
Department of Biology, Membrane Biophysics, Technical University of Darmstadt
Abirami Augsburger
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Nadine Glaisner
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Verena Konetzki
4Cellular Immunotherapy, University Hospital Würzburg, Würzburg, Germany
Sabrina Friedel
4Cellular Immunotherapy, University Hospital Würzburg, Würzburg, Germany
Andrej Besse
6Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland
Lenka Besse
6Department of Medical Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland
Christoph Driessen
Maike Buchner
Kristina Schwamborn
Katja Steiger
Piero Giansanti
2TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, Munich, Germany
Sebastian Theurich
Johannes Waldschmidt
5Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
K. Martin Kortüm
5Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
Michael Hudecek
Hermann Einsele
Marion Högner
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Bernhard Kuster
Angela M. Krackhardt
1Department of Medicine III, TUM University Hospital, Technical University of Munich, Munich, Germany
Judith S. Hecker
Florian Bassermann