To manage autoimmune disease or prevent a transplant rejection, many patients must accept a lifelong trade-off: immunosuppressants reduce immediate threats but increase the risk for infection, cancer, heart disease, and kidney failure.

New science may have found a better way — harnessing the immune system’s own regulatory T cells, or Tregs, to reset the immune system, triggering a long-term benefit without the need for continual drugs.

“It would represent one of the biggest advances in transplantation and autoimmunity for several decades,” said Fadi Issa, DPhil, a professor of transplantation at the University of Oxford, Oxford, England. 

Early evidence shows promise, according to a new review in Frontiers in Science. One of the co-authors, Fred Ramsdell, PhD, shared a Nobel Prize last year for discoveries establishing how Tregs enforce immune tolerance — the immune system’s ability to distinguish the body’s own tissues from threats. When that tolerance fails, autoimmune disease follows — and healthy tissue comes under attack. Transplant patients must overcome this machinery to prevent attacks on donor tissue.

The appeal of Tregs (pronounced tee-regs) is their precision. Their biology evolved to prevent immune attacks against self. “Tregs do not simply turn off immunity,” said immunologist Jeffrey Bluestone, PhD, a coauthor of the new paper and co-founder of Sonoma Biotherapeutics, a biotech company developing Treg therapies. “They actively regulate where, when, and against what immune responses occur.”

Tregs act more like a pharmacy than a single drug, Bluestone said. They use multiple strategies: They release suppressive cytokines, such as interleukin (IL)-10 and transforming growth factor-beta, to tamp down inflammation; they express CTLA-4, a molecule that strips away the activation signals needed to trigger an immune attack; and they soak up IL-2, which effector T cells need to drive autoimmune attacks. They also reshape local metabolism and help repair damaged tissue.

Most of these mechanisms switch on only in inflamed tissue. “Tregs are therefore most potent exactly where autoimmune responses occur,” Bluestone said.

That selectivity is what separates them from immunosuppressants — which suppress immune response “relatively indiscriminately,” said Issa, who authored an accompanying viewpoint. “Which is why they increase the risk of infection and some cancers.”

The Possibilities Don’t End There

Treg therapies promise broad applications throughout medicine.

“Inflammation is a driver of so many chronic diseases,” said immunologist Megan Levings, PhD, a professor in the Department of Surgery and School of Biomedical Engineering at The University of British Columbia, Vancouver, British Columbia, Canada and another co-author of the Frontiers review. “Tregs have the potential to provide therapeutic benefit wherever inflammation has a role.”

That could extend to neurodegeneration, heart disease, and allergies — along with more than 80 autoimmune diseases — adding up to tens of millions of patients who could potentially benefit, Bluestone estimated.

Tregs are being tested in human clinical trials for treating type 1 diabetes, Crohn’s disease, rheumatoid arthritis, transplant rejection, graft-vs-host disease, and amyotrophic lateral sclerosis — and animal studies point to still more indications.

They could be useful for cancer too, with a different mechanism. Because tumors exploit Tregs to evade detection, the conventional goal has been to eliminate them. But Bluestone suggests a more creative strategy: Use Tregs as “Trojan horses” to deliver anticancer drugs such as checkpoint inhibitors, firing a direct hit on unsuspecting tumors.

Timeline and Limitations

Most of these Treg treatments won’t be available anytime soon. “This is a realistic long-term direction rather than something we will see across routine clinical practice in the next few years,” Issa said. He expects early- and mid-phase trials to expand over the next 5-10 years.

Early evidence shows Tregs can be engineered and infused safely into patients. The real test now is proving they provide long-term protection exactly where the body needs it and figuring out why they work for some patients but not others, Issa said.

Manufacturing is a barrier. Autologous Treg therapy requires harvesting a patient’s own cells, multiplying them in a lab, and returning them to the patient — a costly process that must be repeated for each individual. That’s pushing the field toward off-the-shelf products, made in batches from healthy donor cells and ready to infuse into patients. Also under investigation are in vivo approaches, engineering Tregs directly inside the body.

Yet momentum is real. Levings pointed to a positive phase 3 trial (Precision-T) for Orca-Bio’s Orca-T, a transplant graft enriched with Tregs for blood cancer patients. Compared with standard transplants, the Treg graft improved survival rates without chronic graft-versus-host disease. 

The graft (Tregzi) was recently cleared by the FDA, marking the first approved Treg cell therapy.

Issa reported having no disclosures.

Bluestone reported serving as CEO of Sonoma Biotherapeutics, which he co-founded and in which he holds equity. He also reported holding equity in Arcus Biosciences, where he sits on the scientific advisory board, and in Gilead Sciences, where he serves on the board of directors. He reported being named on several Treg cell therapy patents held by UCSF and Sonoma Biotherapeutics.

Levings reported being named on University of British Columbia patents covering chimeric antigen receptors for use in Tregs and serving on the scientific advisory board of Quell Therapeutics, based in London, England.