New resistance mechanism discovered in CAR-T cell therapy
… that could explain why many patients with aggressive B-cell lymphoma do not respond permanently to CAR-T cell therapy.
The results of the study (https://doi.org/10.1016/j.ccell.2025.05.013) led by Professor Dr. Dr. Roland Ullrich - Senior Physician at the Department I of Internal Medicine and associated researcher at the Center for Molecular Medicine Cologne CMMC - open up new possibilities for a combination therapy to further improve the efficacy of this innovative treatment. The results were published on June 12, 2025 in the renowned journal Cancer Cell.
CAR T-cell therapy has revolutionized the treatment of patients with so-called “relapsed or refractory (r/r)” aggressive B-cell lymphomas - i.e. lymphoma diseases defined by disease relapses or therapy-resistant courses - in recent years. This involves genetically modifying the body's own T-cells so that they can specifically recognize and destroy the cancer cells. CAR T cells directed against the B-cell marker CD19 in particular have proven to be extremely effective and have been approved worldwide for various aggressive B-cell lymphomas. However, only around half of patients benefit from this therapy in the long term. Around 50 percent of patients treated with CAR-T cells do not show a lasting response and suffer a relapse or die from their disease despite treatment. The reasons for this can be manifold and require intensive research efforts.
In order to investigate these unanswered questions, the Cologne research team, which includes the first authors of the paper, Dr. David Stahl, Dr. Philipp Gödel and Dr. Hyatt Balk-Want, analyzed patient samples before and after CAR-T cell treatment using state-of-the-art cell biology methods. Dr. Hyatt Balke-Want is one of six Awardees in 2025 in the Career Advancement Program at the Center for Molecular Medicine Cologne (CMMC).
The scientists discovered a specific group of immune cells, so-called CSF1R-positive myeloid monocytic cells (also known as LAMM cells), which were conspicuously increased in patients without a sustained response. The researchers were able to show that these LAMM cells specifically restrict the function of the CAR-T cells that act therapeutically against the lymphoma and are therefore partly responsible for the failure of CAR-T cell therapy.
"Our results show that these LAMM cells form a kind of protective shield for the tumor against the CAR-T cells. They inhibit the effect of the CAR-T cells and thus prevent the effectiveness of CAR-T cell therapy," explains Prof. Ullrich, who is the last author of the study.
A promising therapeutic approach was shown in the preclinical mouse model: if the effect of the LAMM cells is specifically blocked with an already approved drug - a so-called CSF1R inhibitor - the effectiveness of the CAR-T cells is significantly improved. These findings are an important step in the direction of a new combination therapy in which CAR-T cells could be used together with a CSF1R inhibitor.
The project is funded by the Collaborative Research Center 1530, which aims to develop new targeted therapeutic approaches through the discovery of new pathomechanisms and thus improve the cure rate of patients with prognostically unfavorable B-cell neoplasias. The aim is now to test this approach in a clinical trial in patients with aggressive B-cell lymphoma.
Find out more about Dr. Hyatt Balke-Want´s research project at the Center for Molecular Medicine Cologne.
Find out more about Prof. Roland Ullrich´s research project at the Center for Molecular Medicine Cologne.
Original Publication
David Stahl, Philipp Gödel, Hyatt Balke-Want, Rahil Gholamipoorfard, Paul Segbers, Luis Tetenborg, Mirjam Koker, Janina Dörr, Lisa Gregor, Daniel Bachurski, France Rose, Adrian G. Simon, Zinaida Good, Josefine Jakob, Björn Häupl, Marieke Nill, Ruth Flümann, Tobias Riet, Dinah Lange, Stuart J. Blakemore, Herrad Baurmann, Conrad-Amadeus Voltin, Nicole Potter, Lilli Schlözer, Max Freihammer, Svenja Wagener-Ryczek, Andra-Iza Iuga, Jan-Michel Heger, Hanna Ludwig, Julia K. Schleifenbaum, Jessica Propp, Paul J. Bröckelmann, Ron D. Jachimowicz, Gero Knittel, Sven Borchmann, Sabine Merkelbach-Bruse, Christian Pallasch, Martin Peifer, Jan Rybniker, Alexander Quaas, Mark Nitz, Johannes Brägelmann, Werner Müller, Thorsten Persigehl, Katarzyna Bozek, Sebastian J. Theobald, Reinhard Büttner, Thomas Oellerich, Michael Hallek, Sebastian Kobold, Markus Chmielewski, Hans Christian Reinhardt, Crystal Mackall, Nima Abedpour, Peter Borchmann, Roland T. Ullrich, “CSF1R+ myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma”, Cancer Cell, 2025 (https://doi.org/10.1016/j.ccell.2025.05.013)
This message has been modified by the CMMC (K. Heber & D. Grosskopf-Kroiher) and is based on the text by the press and communications team of the University Hospital Cologne (Mirko Ristau, Deputy Press Spokesman, Team Leader Corporate Communications, Corporate Communications and Marketing Department - original German version here).