Sylvester Comprehensive Cancer Center Researchers Discover Why Some Lymphomas Resist CAR T-cell Treatment
Key Takeaways
- Sylvester Comprehensive Cancer Center researchers identified a genetic alteration that helps some large B-cell lymphomas resist CAR T-cell therapy.
- The multi-center study found that loss of the RHOA gene helps tumors evade immune attack by reducing CD19 and disrupting key immune responses.
- Published in Blood Cancer Discovery, the findings provide new insight into treatment resistance and potential future therapeutic strategies.
For many patients with large B-cell lymphoma, CAR T-cell therapy has been life-changing. The treatment works by reprogramming a patient’s own immune cells to recognize and attack cancer cells carrying a protein called CD19. For some people, it leads to long-lasting remission. For others, the cancer finds a way to resist the treatment or come back later.
A new multicenter study led by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, in collaboration with Memorial Sloan Kettering Cancer Center and Moffitt Cancer Center, has uncovered one of the tricks lymphoma can use to survive. The team identified a gene called RHOA that appears to help tumors evade CAR T-cell therapy when it is lost or damaged.
Their findings reveal how a single genetic change can make cancer cells harder to recognize, harder to eliminate and better able to create an immune environment that works in their favor. The study provides new insight into why some patients experience treatment resistance and points to new avenues for investigation.
The study was published in Blood Cancer Discovery, a journal of the American Association for Cancer Research.
“One of the biggest challenges in cancer research is understanding why a treatment can be remarkably effective for some patients and fall short for others,” said Jonathan Schatz, M.D., senior author of the study, Sylvester researcher in the Division of Hematology and professor of hematology at the Miller School. “We wanted to understand what the tumor was doing to survive, and this study gave us a window into one of those survival strategies.”
Researchers had previously noticed that patients whose lymphoma returned after CAR T-cell therapy were more likely to have deletions in RHOA. About one in six newly diagnosed cases of large B-cell lymphoma also carry this alteration, suggesting it plays an important role in the disease long before treatment begins.
To understand why, the team analyzed patient samples and created laboratory models that mimicked the genetic loss seen in tumors. CAR T cells rely on CD19 to identify their target. Without it, they struggle to recognize lymphoma cells.
When researchers reduced RHOA activity, the cancer cells produced less CD19. The change did not eliminate CD19 completely, but it lowered the amount displayed on the cell surface. As a result, CAR T cells were less effective at finding and killing the cancer. Experiments in the laboratory and in preclinical models confirmed that lymphoma cells with reduced RHOA activity were more resistant to CAR T-cell therapy.
The findings are particularly important because CAR T-cell therapy remains a critical treatment option for patients with relapsed or treatment-resistant lymphoma. Understanding why some tumors evade immune attack could help researchers develop more effective approaches in the future.
“For patients whose disease returns after CAR T-cell therapy, we often have limited answers about why the treatment stopped working,” said Juan Pablo Alderuccio, M.D., co-author of the study, hematologist, lymphoma specialist at Sylvester and associate professor of clinical medicine at the Miller School. “Research like this helps us move closer to understanding the biology behind resistance and, ultimately, how we might overcome it.”
Rewiring the Neighborhood
Cancer cells live within a complex community of immune cells, blood vessels and supporting tissues known as the tumor microenvironment.
Using advanced single-cell sequencing technology and preclinical models, the researchers discovered that RHOA loss dramatically changed this environment. Tumors with reduced RHOA activity developed many of the same features seen in patients whose cancers resisted CAR T-cell treatment.
“We often think about resistance as something happening inside an individual cancer cell,” Dr. Schatz said. “But tumors are part of an ecosystem. What happens around the tumor can be just as important as what happens within it.”
The immune system seemed active, with high levels of inflammatory signals. Yet that activity failed to translate into an effective anticancer response. Instead, communication between immune cells became less coordinated, and CAR T cells showed signs of impaired growth and function.
Why This Research Matters
CAR T-cell therapy depends on recognizing CD19 on lymphoma cells, but some tumors resist treatment or return after an initial response.
Researchers found that loss of RHOA can lower CD19, weaken the tumor’s response to immune signals and reshape the surrounding immune environment.
The findings identify mechanisms that researchers can investigate as they explore future strategies for overcoming treatment resistance.
Cancer That Stops Listening
One of the study’s most surprising discoveries involved interferon gamma, an immune signaling molecule that normally helps the body recognize and eliminate cancer cells. Healthy immune responses use interferon gamma to instruct cells to display warning signals called MHC class I molecules. These molecules tell killer T cells that something is wrong and that the cell should be destroyed.
But lymphoma cells with reduced RHOA activity became less responsive to interferon gamma. They failed to fully activate key immune pathways and showed lower levels of MHC class I molecules on their surfaces.
In effect, the cancer cells stopped listening to an important immune alarm system. Without those warning signals, cancer cells become harder for the immune system to identify and remove.
The researchers found that RHOA loss gives lymphoma cells more than one way to avoid treatment.
First, it reduces CD19, the target that CAR T cells are designed to recognize. Second, it weakens the tumor’s response to immune signals that normally help the body detect and attack cancer cells. Together, these changes create a powerful survival strategy.
This may help explain why RHOA deletions are found not only in patients whose cancers resist CAR T-cell therapy, but also in many newly diagnosed cases of large B-cell lymphoma.
An Opportunity for New Treatments
The researchers also uncovered a potential weakness. Loss of RHOA made lymphoma cells more dependent on a growth pathway known as PI3K-AKT-mTOR. When the team blocked parts of that pathway with targeted drugs in laboratory studies, CD19 levels increased again.
“One of the exciting aspects of this discovery is that it points us toward testable strategies,” said Jay Spiegel, M.D., co-author of the study and assistant professor in the Division of Transplantation and Cellular Therapy at the Miller School. “When we identify how a tumor adapts, we can begin thinking about ways to reverse those changes or make the cancer visible to the immune system again.”
Although more research is needed, the findings raise the possibility that combining CAR T-cell therapy with targeted treatments could help restore the cancer’s visibility to the immune system and improve outcomes for patients.
Looking Ahead
The study offers one of the clearest explanations yet for why some lymphomas resist CAR T-cell therapy. By reducing CD19, weakening immune surveillance and reshaping the tumor microenvironment, loss of RHOA gives cancer multiple ways to avoid destruction.
More importantly, the work highlights how understanding the genetics of a tumor can reveal new opportunities for treatment.
“Cancer survives by adapting,” Dr. Schatz said. “Every time we uncover one of those adaptations, we can find new ways to go after it in the clinic. The more we understand how tumors evade the immune system, the better equipped we are to design therapies that can overcome those defenses.”
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Tags: cancer research, cancer survivorship, CAR T cells, diffuse large B cell lymphoma, Dr. Jay Spiegel, Dr. Jonathan Schatz, Dr. Juan Pablo Alderuccio, hematology, immune system, lymphoma, lymphoma research, Sylvester Comprehensive Cancer Center, Sylvester Survivorship and Supportive Care Institute