Study: New protocol for Treg expansion uses targeted immunotherapy to reduce transplant complications

MIAMI, FLORIDA (EMBARGOED UNTIL THURSDAY, NOV. 27, 2025) – In preclinical studies, researchers found that priming the immune system with a Treg-expanding therapy before stem cell transplant boosted survival, protected vital organs, and promoted a balanced gut microbiome—offering hope for safer, more effective treatment of blood cancers. The study, led by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, and collaborating organizations, is highlighted on the cover of the Nov. 27, 2025, issue of the journal, Blood.

The new protocol focuses on improving outcomes for patients who undergo allogeneic hematopoietic stem cell transplantation (aHSCT), a procedure often used to treat blood cancers and other serious conditions.

Transplant patients face a risk of developing graft-versus-host disease (GVHD), a complication where the new immune cells attack the patient’s own tissues. Traditionally, doctors use strong medications to suppress the immune system and prevent GVHD, but these drugs can cause side effects and leave patients vulnerable to infections.

Led by senior author, Robert Levy, Ph.D., a researcher at Sylvester and a professor of microbiology and immunology at the Miller School, the multi-institutional research team developed a new protocol that uses targeted immunotherapy to help the body’s own regulatory T cells (Tregs) expand before transplant. Tregs are a type of immune cell that helps keep the immune system in balance. By increasing the number of Tregs in advance, the body is better prepared to handle the transplant and reduce the risk of GVHD.

“Our approach is about helping the patient’s own immune system create a safer environment for the stem cell transplant,” Levy explained. “We’re not just suppressing the immune response—we’re guiding it in key tissues involved following the transplant to promote success.”

The researchers used preclinical models to test a combination of two agents: TL1A-Ig fusion protein and low-dose IL-2. These agents stimulate specific receptors (TNFRSF25 and CD25) on Tregs, encouraging them to multiply and become more active. The expanded Tregs were found in key tissues such as the colon, liver and eye—areas often affected by GVHD.

The protocol led to several positive outcomes in preclinical studies:

• Higher survival rates after transplant
• Lower GVHD scores and less weight loss
• Better tissue health and integrity
• A more diverse and healthy gut microbiome

“We saw that expanding Tregs before transplant helped protect vital tissues organs and supported a healthier microbiome,” Levy said. “This could mean fewer complications and better recovery for patients.”

This research is significant because it offers a new way to prevent GVHD without relying solely on broad immune-suppressing drugs. By using targeted immunotherapy to expand Tregs, the protocol may reduce side effects and improve the quality of life for transplant patients.

Another key finding is that the protocol does not interfere with the body’s ability to address cancer cells—a process known as graft-versus-leukemia (GVL). Maintaining GVL is crucial for preventing relapse in patients with blood cancers.

“Our goal is to make transplants safer while still allowing the patient’s immune system to do its job against cancer,” Levy noted. “We’re working toward therapies that are both effective and practical for real-world use.”

Moving Toward Personalized Medicine

Unlike older methods that require collecting and manipulating donor cells outside the body, Levy’s protocol works by expanding the patient’s own Tregs in vivo—inside the body—before the transplant. This approach could simplify treatment and make it more accessible.

The research also highlights the role of the gut microbiome in transplant outcomes. Patients who received the Treg expansion protocol had a more diverse and balanced microbiome, a finding that is increasingly recognized as important for immune health.

“Personalized medicine is about tailoring treatments to each patient’s needs,” Levy said. “By supporting the immune system and microbiome, we can help patients recover more smoothly.”

He and colleagues are working to translate these findings into clinical trials. The hope is that this protocol will become part of standard care for patients undergoing stem cell transplants, leading to fewer complications and better long-term outcomes.

“We’re excited to continue this work and collaborate with clinicians to bring new therapies to patients,” Dr. Levy concluded. “Every step forward brings us closer to safer, more effective transplants.”

Levy’s team included researchers from other leading institutions including Sloan Kettering Institute and Memorial Sloan Kettering in New York, Weill Cornell Medical College and Fred Hutchinson Cancer Center in Seattle.

Read more about Sylvester research on the InventUM blog and follow @SylvesterCancer on X for the latest news on its research and care.

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