Genetically modified immune cells can offer precious additional time to patients with advanced multiple myeloma. However, these therapies lose their impact as the molecules on cancer cells that immune cells recognize gradually vanish. Researchers at the Technical University of Munich (TUM) have now identified one of the molecular mechanisms behind this process. In an initial study they succeeded in blocking it using an existing cancer drug.
CAR T cell therapies are becoming increasingly important in cancer treatment. The approach involves modifying a patient’s own T cells in the lab. They are equipped with artificial receptors that “recognize” specific molecules on cancer cells. These engineered immune cells multiply in the body and destroy the malignant cells. In the case of multiple myeloma, the target molecule is BCMA – short for B Cell Maturation Antigen.
“BCMA is well suited as a target for CAR‑T therapy because it is highly specific to malignant plasma cells," explains Prof. Florian Bassermann, Director of the Department of Internal Medicine III at TUM University Hospital. “But cancer immunotherapy triggers rapid evolution inside the body.” The engineered T cells exert selective pressure, meaning that cancer cells that have little or no BCMA on their surface proliferate while others are destroyed. As a result, the therapy gradually stops working. CAR T cell therapies are currently only used for multiple myeloma after other treatment options have failed. They can prolong life – sometimes by years – but have not yet been able to permanently eliminate the cancer.
New mechanism discovered
"Until now, it wasn’t clear how BCMA disappears from the membrane of some plasma cells," says Dr. Leonie Rieger, first author of the study. "We were able to show that the ubiquitin-proteasome system is responsible. The mechanism we discovered can degrade BCMA surprisingly quickly."
The ubiquitin-proteasome system is a complex network of molecules inside cells that determines which proteins are broken down and which are preserved. Until recently, it was thought to act only within the cell. The new study shows for the first time that it also affects molecules on the cell surface.
Proteasome inhibitor halts BCMA loss
The ubiquitin-proteasome system is already a known target in cancer treatment. For example, the drug carfilzomib is approved for use in multiple myeloma. It works by preventing the breakdown of specific proteins in diseased plasma cells, which often leads to cell death.
The researchers were able to show in laboratory and animal experiments that carfilzomib can also prevent the degradation of BCMA.
Patients responded to therapy again
In the next phase of the study, the researchers tested this approach in ten patients. All had previously received a CAR T cell therapy targeting BCMA, which had stopped working. After in-label treatment with carfilzomib, the cancer cells in all ten patients once again displayed BCMA on their surface. In six of the patients – those who still had enough CAR T cells in their system – the therapy became effective again.
“For many patients whose CAR T therapy has already reached its limits, this could offer new hope,” says Dr. Judith S. Hecker, Head of Cellular Immunotherapy at the Department of Internal Medicine III. “However, because our study involved only a small number of participants, it’s still unclear which patients are most likely to benefit from treatment with carfilzomib.”
“We now want to investigate whether our findings hold up in larger studies,” adds Florian Bassermann. “We’re also exploring whether it might make sense to administer the drug right at the start of CAR T cell therapy.” His team suspects that the newly discovered mechanism may also degrade other surface molecules – and if so, it could help improve other forms of immunotherapy as well.
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Subject matter expert:
Prof. Dr. Florian Bassermann
Technical University of Munich
TUM Klinikum
Department of Internal Medicine III
Phone: +49 89 4140 4111
florian.bassermann@tum.de
med3.mri.tum.de
TUM Corporate Communications Center contact:
Paul Hellmich
Media Relations
Tel. +49 (0) 89 289 22731
presse@tum.de
www.tum.de
Blood
Experimental study
Animals
Boosting CAR T-cell efficacy by blocking proteasomal degradation of membrane antigens
29-Jan-2026
F.B. received honoraria and/or travel/accommodation expenses from Bristol Myers Squibb (BMS), AbbVie, Amgen, and Johnson & Johnson. J.S.H. received consulting fees, speakers’ fees, and/or travel accommodation expenses from Johnson & Johnson, BMS, Kite/Gilead, AbbVie, Servier, Novartis, Roche, Iovance, Immatics, Philogen, Boehringer Ingelheim, Immunocore, Autolus, and Kyverna Therapeutics. J.W. received honoraria from Janssen, Sanofi, Takeda, Pfizer, Oncopeptides, SkylineDx, GlaxoSmithKline (GSK), Janssen, Pfizer, and BeiGene; and research support from BMS. M. Hudecek and S.F. are listed as inventors on patent applications and granted patents related to CAR T-cell technologies that have been filed by the Fred Hutchinson Cancer Research Center, Seattle, Washington (M. Hudecek) and the University of Würzburg, Würzburg, Germany (M. Hudecek and S.F.), which have been partly licensed by the industry. M. Hudecek is a cofounder and equity owner of T-CURX GmbH (Würzburg, Germany). S.F. is an employee of T-CURX GmbH (Würzburg, Germany). M. Hudecek received speaker honoraria from BMS, Janssen, and Kite/Gilead. K.M.K. received honoraria and/or research support from AbbVie, BMS, GSK, Janssen, Novartis, Pfizer, Sanofi, Takeda, and Stemline Therapeutics. H.E. received consulting fees and/or advisory honoraria from BMS/Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, and Novartis; research funding from BMS, Janssen, Amgen, GSK, and Sanofi; and travel support from BMS/Celgene, Janssen, Amgen, and Sanofi. The remaining authors declare no competing financial interests.