(Press-News.org) Researchers at MUSC Hollings Cancer Center have identified a signaling loop involved in the growth and persistence of leukemia cells – and developed a novel immunotherapy that can disrupt that loop to boost immune function and improve survival. The findings, published in Nature Communications, offer new hope for treating and preventing cancer.
Hollings researcher Sophie Paczesny, M.D., Ph.D., co-leader of the Cancer Biology and Immunology Research Program, led the multidisciplinary research team. Paczesny, a pediatric hematologist-oncologist and bone marrow transplant expert, has spent her career fighting one of the most difficult-to-treat blood cancers: acute myeloid leukemia (AML).
“I’ve seen too many patients – especially children – suffer from AML,” Paczesny said. “Unlike other forms of leukemia that respond well to chemotherapy or CAR-T cell therapy, AML has proven much more stubborn.”
A challenging diagnosis
AML is a fast-growing and aggressive form of blood cancer. Even with treatment, the cancer often comes back. This high rate of relapse can be traced to leukemia stem cells, a small group of cells that can survive chemotherapy by hiding in the bone marrow. These “hidden” cells then send out signals that both help the cancer grow and prevent the immune system from fighting back.
The new study revealed a key pathway used by these leukemia cells: the loop between a protein called IL-33 and its receptor IL1RL1. The researchers showed that IL1RL1, which is present in high amounts on AML cells and in the tumor’s protective environment, is key to its treatment resistance.
“The more aggressive the leukemia, the more IL1RL1 we saw,” Paczesny said. “And, in AML, it forms a damaging feedback loop. The leukemia starts and keeps growing because of stress that triggers a self-sustaining loop between IL-33 and its receptor, which also creates an immune environment that helps the cancer avoid being attacked.”
Breaking the loop
To break the feedback loop, the researchers developed a novel immunotherapy using a lab-made antibody. Known as a bispecific antibody, the treatment worked via dual means:
It blocked the IL-33/IL1RL1 signal by targeting and killing leukemia cells carrying IL1RL1.
It prompted the immune system to attack the cancer cells by activating infection-fighting T-cells like CD8+.
“These leukemia cells have learned to create a protective environment that helps them grow and avoid treatment,” Paczesny said. “We developed a bispecific antibody that can break through that environment and target the cells directly.”
In lab and mouse models, this dual-targeting approach not only destroyed the cancer cells but also removed their protective immune bubbles, making it easier for the body to fight back. The antibody slowed or stopped leukemia cell growth, limited immune suppression and reduced relapse rates. Even in tough cases where leukemia had already taken hold, the new therapy improved survival. And it did so without causing major side effects.
A new way forward
This study showed that targeting the signaling pathway used by leukemia stem cells can lead to better care for cancer patients. The researchers created an immunotherapy that not only killed cancer cells but also disrupted the immune system’s ability to protect them. By blocking a hidden cancer signal, that therapeutic may one day stop leukemia in its tracks.
The promising results offer an approach that could improve treatments for AML as well as other cancers with a similar tumor microenvironment.
“IL1RL1 is expressed in other cancers too: colorectal, lung, ovarian, even brain cancers,” Paczesny said. “This could be a game-changer for many difficult-to-treat cancers.”
The researchers also see the new antibody as overcoming some of the challenges of existing treatments. For instance, its low toxicity could make it safer to use and more acceptable to patients. It is also easier and less expensive to produce.
“Chemotherapy is toxic, and bone marrow transplants can come with serious risks. With immunotherapies like CAR-T cells, you need a customized treatment for each patient, which is expensive and time-consuming,” Paczesny explained. “Our treatment is an off-the-shelf drug. And it targets cells just enough to fight cancer without destroying the whole system. This could mean less time in the hospital, fewer side effects and a better quality of life.”
More work is needed before the antibody can be used with patients, but this study is a major step forward. It could eventually lead to new treatments that target cancer cells at their roots and offer an option when standard treatments fail. The researchers are already working on next steps and are hopeful that Phase I clinical trials are on the horizon.
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About MUSC Hollings Cancer Center
MUSC Hollings Cancer Center is South Carolina’s only National Cancer Institute-designated cancer center with the largest academic-based cancer research program in the state. With more than 230 faculty cancer scientists from 20 academic departments, it has an annual research funding portfolio of more than $50 million and sponsors more than 200 clinical trials across the state. Hollings specialists include surgeons, medical oncologists, radiation oncologists, radiologists, pathologists, psychologists and other clinical providers equipped to provide the full range of cancer care from diagnosis to survivorship. Hollings offers state-of-the-art cancer screenings, diagnostics, therapies and surgical techniques within its multidisciplinary clinics. Dedicated to preventing and reducing the cancer burden statewide, the Hollings Office of Community Outreach and Engagement works with community organizations to bring cancer education and prevention information to affected populations throughout the state. For more information, visit hollingscancercenter.musc.edu.
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