Established cancer drug reactivates immunotherapy

Professor Florian Bassermann and his team are researching the role of the ubiquitin system in cancer. Insights from their basic research are quickly benefiting patients as well.
Photo Credit: Kathrin Czoppelt / TUM Klinikum

Scientific Frontline: Extended "At a Glance" Summary

The Core Concept: Researchers have identified that an existing cancer drug, carfilzomib, can restore the efficacy of CAR-T cell therapy in multiple myeloma patients by preventing cancer cells from hiding their surface markers.

Key Distinction/Mechanism: A common resistance mechanism in immunotherapy involves cancer cells degrading specific surface antigens (like BCMA) via the ubiquitin-proteasome system, effectively becoming invisible to engineered T cells. Unlike therapies that require new drug discovery, this method utilizes carfilzomib—a known proteasome inhibitor—to block this degradation process, restabilizing the antigens on the cell surface and allowing the CAR-T cells to recognize and attack the cancer again.

Origin/History: The findings were published in the journal Blood in 2026 by a team led by Prof. Florian Bassermann and Dr. Leonie Rieger at the Technical University of Munich (TUM).

Major Frameworks/Components:

• CAR-T Cell Therapy: A treatment where a patient's T cells are genetically modified to target cancer cells.
• BCMA (B Cell Maturation Antigen): The specific protein target on multiple myeloma cells.
• Ubiquitin-Proteasome System: The intracellular network responsible for degrading proteins, identified here as the cause of BCMA loss.
• Carfilzomib: An approved drug that inhibits the proteasome, preventing antigen degradation.

Branch of Science: Oncology, Immunology, Molecular Biology, Pharmacology.

Future Application: This approach allows for the immediate concurrent use of carfilzomib to extend the effectiveness of CAR-T therapy for relapsed patients. Future trials will investigate whether administering the drug at the start of therapy prevents resistance altogether and if the mechanism applies to other cancer types.

Why It Matters: CAR-T cell therapy is a powerful but expensive "last resort" treatment that often fails when cancer cells evolve to hide their targets. By repurposing an approved drug to reverse this specific resistance mechanism, this discovery offers a rapid, clinically accessible strategy to prolong patient survival without the decade-long timeline required to develop new medications.

A myeloma cell with BCMA (green) on its surface.
Image Credit: Leonie Rieger / TUM

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. 

Professor Florian Bassermann and his team are researching the role of the ubiquitin system in cancer. Insights from their basic research are quickly benefiting patients as well. 

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 myelomas. 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. 

Published in journal: Blood

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

Authors: Leonie Rieger, Kilian Irlinger, Franziska Füchsl, Marlene Tietje, Anna Purcarea, Nicolas Barbian, Melanie Faber, Carolin Vogelsang, Lisa Pfeuffer, Sonja Stotz, Oleksandra Karpiuk, Tobias Schulze, Abirami Augsburger, Nadine Glaisner, Verena Konetzki, Sabrina Friedel, Andrej Besse, Lenka Besse, Christoph Driessen, Maike Buchner, Kristina Schwamborn, Katja Steiger, Piero Giansanti, Sebastian Theurich, Johannes Waldschmidt, K. Martin Kortüm, Michael Hudecek, Hermann Einsele, Marion Högner, Bernhard Kuster, Angela M. Krackhardt, Judith S. Hecker, and Florian Bassermann

Source/Credit: Technische Universität München

Reference Number: ongy021126_03

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