The cells essentially weaken themselves in the process of fighting.
In the long human struggle against cancer, one of medicine's most ingenious tools—engineering a patient's own immune cells to seek and destroy tumors—has been undermined by a quiet act of self-defeat. Researchers at the University of Maryland have now identified the molecular mechanism behind this failure: a protein called cathepsin b that causes CAR T-cells to absorb fragments of the very cancer cells they attack, dulling their own effectiveness. By blocking this protein, scientists restored the cells' durability and fighting power in preclinical models, opening a path toward clinical trials that could matter deeply to patients who have relapsed after treatment.
- Most patients who receive CAR T-cell therapy relapse within five years, exposing a critical durability gap in one of oncology's most celebrated advances.
- Advanced imaging revealed a startling self-sabotage: engineered immune cells tear pieces from cancer cells and absorb them, weakening their own tumor-fighting capacity in the process.
- The protein cathepsin b was identified as the molecular trigger for this fragment absorption, giving researchers a precise and actionable target.
- Blocking cathepsin b in modified T-cells caused them to remain active longer and attack tumors more aggressively in both lab and animal models.
- The University of Maryland Greenebaum Cancer Center is already running first-in-human CAR T-cell trials, creating a ready pathway to test this discovery in patients with recurrent B-cell lymphoma.
A research team at the University of Maryland School of Medicine has identified a molecular flaw that quietly undermines CAR T-cell therapy—a treatment in which a patient's own immune cells are reprogrammed to hunt and destroy cancer. While the therapy works remarkably well for some, most patients relapse within five years, and the reasons have remained elusive.
The answer emerged from watching the cells at work. Research fellow Kenneth Dietze, working in Tim Luetkens's lab, discovered that CAR T-cells engage in a form of self-sabotage: they tear fragments from cancer cell surfaces and absorb them, a process that diminishes their ability to keep fighting tumors. The culprit turned out to be a protein called cathepsin b. When researchers blocked it, the cells stopped absorbing those fragments, stayed active longer, and attacked cancer more aggressively in laboratory and animal models. The findings were published in Signal Transduction and Targeted Therapy.
Collaborators at the University of Maryland, College Park, provided advanced imaging that made the fragment-tearing process visible for the first time—evidence that allowed the team to understand the mechanism and test their intervention. Luetkens, who also directs research at the Greenebaum Comprehensive Cancer Center, framed the discovery as one piece of a larger puzzle scientists are still assembling around how engineered immune cells behave and how to improve them.
The center's executive director called the results real progress toward better patient outcomes, while noting the essential next step: human clinical trials. That pathway already exists—the center is conducting a first-in-human CAR T-cell study for patients with recurrent B-cell lymphoma. For people with blood cancers that have returned after treatment, this preclinical finding offers a concrete and credible direction forward.
A team at the University of Maryland School of Medicine has zeroed in on a molecular problem that undermines one of cancer medicine's most promising weapons. CAR T-cell therapy—a treatment in which doctors reprogram a patient's own immune cells to hunt down and destroy cancer—works remarkably well for some people. But most patients who receive it relapse within five years, and researchers have been searching for ways to make the therapy stick.
The breakthrough came from watching what happens at the cellular level. Kenneth Dietze, a research fellow in Tim Luetkens's lab at UMSOM, discovered that CAR T-cells engage in a self-sabotaging behavior: they tear off fragments from the surface of cancer cells and incorporate those pieces into themselves. It sounds like a minor detail, but it has major consequences. When the T-cells absorb these cancer cell fragments, they become less effective at their primary job—attacking tumors. The cells essentially weaken themselves in the process of fighting.
The research team identified the culprit: a protein called cathepsin b. When they blocked this protein in the modified T-cells, something shifted. The cells stopped tearing off and absorbing cancer cell fragments. More importantly, they stayed active longer and fought cancer more aggressively in both laboratory and animal models. The findings appeared in Signal Transduction and Targeted Therapy, a peer-reviewed journal.
Luetkens, an associate professor of microbiology and immunology at UMSOM and director of research and development at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, emphasized the broader significance. "Genetically engineered cells are a promising new way to treat cancer and autoimmune diseases," he said. "However, scientists are still figuring out how these cells work and how to make them better." This discovery addresses one piece of that puzzle.
The research was a collaborative effort. Scientists at the University of Maryland, College Park, contributed advanced imaging techniques that allowed the team to directly observe the process of T-cells tearing fragments from cancer cells—work that would have been impossible to visualize just a few years ago. The imaging gave them the visual evidence they needed to understand the mechanism and then test whether blocking cathepsin b would change the outcome.
Taofeek Owonikoko, executive director of the cancer center, called the findings "real progress that could ultimately improve durability and outcomes for our patients." But he was careful to note the next step: these results need to move into human clinical trials. The center is already running a first-in-human study testing CAR T-cell therapy in patients with recurrent or difficult-to-treat B-cell lymphoma, so the pathway to testing this new approach exists.
For patients with blood cancers that have resisted standard treatment or returned after initial therapy, this represents a concrete lead. The five-year relapse rate has been a stubborn problem in the field. If blocking cathepsin b can extend the durability of CAR T-cell therapy—making the engineered cells stay active longer and fight more effectively—it could change outcomes for people who have run out of other options. The work is still in preclinical stages, but the direction is clear.
Notable Quotes
Genetically engineered cells are a promising new way to treat cancer and autoimmune diseases. However, scientists are still figuring out how these cells work and how to make them better.— Tim Luetkels, MD, Associate Professor of Microbiology and Immunology at UMSOM
While these findings need to be translated into human clinical trials, this is real progress that could ultimately improve durability and outcomes for our patients.— Taofeek K. Owonikoko, MD, PhD, Executive Director of UMGCCC
The Hearth Conversation Another angle on the story
So the CAR T-cells are actually eating pieces of the cancer cells they're supposed to be killing?
Not eating exactly, but absorbing fragments from the cancer cell surface. It's like they're picking up debris from the battlefield and carrying it with them, which makes them less effective at the next fight.
And blocking this cathepsin b protein stops that from happening?
Yes. When you block it, the T-cells don't tear off those fragments in the first place. They stay cleaner, stay active longer, and keep fighting.
Why would the T-cells do this in the first place? What's the evolutionary or biological reason?
That's a good question. The mechanism isn't fully explained in the research, but it's likely a side effect of how T-cells naturally interact with other cells. The engineering makes them aggressive, but it doesn't eliminate all their normal behaviors.
How far away are we from using this in actual patients?
The findings are solid in lab and animal models, but human trials are the next step. The cancer center is already running CAR T-cell trials for lymphoma patients, so they have the infrastructure to test this modification relatively soon.
What happens if this works in humans?
If it extends how long the engineered cells stay effective, it could reduce the five-year relapse rate that's been a major limitation of the therapy. That would be significant for patients with blood cancers that have already resisted other treatments.