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.
Kathrin Czoppelt / TUM Klinikum 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.
Leonie Rieger / TUM 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.
Rieger, L. et al. Boosting CAR T-cell efficacy by blocking proteasomal degradation of membrane antigens . Blood 147, 534-546 (2026). DOI:10.1182/blood.2024027616
- Prof. Florian Bassermann is Director of the D epartment of Internal Medicine III, Hematology and Oncology at TUM Hospital and a member of the TUM School of Medicine and Health .
- He also heads a working group at TranslaTUM , TUM's Central Institute for Translational Cancer Research. Here, researchers from medicine, engineering, and the natural sciences work together to fight cancer, with the goal of rapidly turning basic research findings into clinical applications.
- Since 2024, Prof. Bassermann also heads the DFG funded transregional collaborative research center UbiQancer (TRR 387) , which focuses on how the ubiquitin system can be harnessed for cancer therapies.
