T Regulatory Cells Join the Mainstream

Just 70 years ago, cancers of the blood were essentially untreatable while other cancers, of solid organs for instance, could be cut out with surgery or burned out with radiation. Eventually chemotherapeutic agents became capable of killing a cancer without killing the patient, but they were brutal. Then along came blood and marrow transplantation which could give patients a new lease on life. However, they required immunosuppressive agents to keep the patient’s immune system from rejecting the transplant—and those came with serious side effects. Consistent steps forward but always with asterisks.

Today some high-risk patients at Stanford with severe cancers, including leukemias, lymphoma, and myelodysplastic syndrome, are enrolled in a Phase 2 randomized clinical trial in which they forgo immunosuppression in favor of treatment with T regulatory cells, known as T regs, thanks to work by a team led by Everett Meyer, MD, PhD, assistant professor of blood and marrow transplantation.

Progress has been slow and steady. According to Meyer, “It’s actually been a 20-year effort. The proof of concept was done in 2003, and the trial itself opened in 2011. After I joined as faculty in 2015 and the person who had opened the trial left, I revamped it and did some basic science to fix some problems. Once we reopened the trial we had pretty good success.”

Patients in the trial are quite sick, Meyer explains, and their course is rigorous: “They’ve either failed an initial therapy or they’re so high risk that we expect their disease to come back. They need a bone marrow transplant, and we have to get donor grafts into them and then prevent their grafts from causing graft-versus-host disease, a major complication. We also need to allow their new donor immune system the space and freedom to attack and kill the cancer. That graft-versus-leukemia effect is the secret sauce of our transplant.”

Once a patient receives a bone marrow transplant, T regs attempt to teach the patient’s new immune system how to regrow in a way that will help the anti-leukemia response and prevent complications. Using immunosuppressive medications, on the other hand, is a “strategy that essentially says we’re going to cripple the immune system just enough to make it work,” according to Meyer.

Not all patients in the ongoing randomized trial get to skip immunosuppressive medications. Only half the patients get T regs alone while the other half get T regs plus a single-agent immunosuppressive. By comparing the two groups, Meyer will be able “to understand how effective these T regulatory cells are. So far, we’ve seen very few mild cases of graft-versus-host disease in the 17 patients we’ve treated.”

T regulatory cells have shown promise in newer frontiers such as solid organ transplant and islet tolerance, and the treatment of autoimmune disorders such as rheumatic disease or Type 1 diabetes. Meyer considers himself fortunate to have collaborators in many divisions: Seung Kim, MD, PhD, professor of developmental biology; Justin Annes, MD, PhD, assistant professor of endocrinology; Sam Strober, MD, professor of rheumatology and immunology; Robert Negrin, MD, professor and chief of blood and marrow transplantation; and Judith Shizuru, MD, professor of blood and marrow transplantation, have been “guiding forces.”

He is especially pleased to work with “the people who do cell therapy, because they’re the quiet, unsung, committed heroes moving things forward. I know certain things, but I know I don’t know more. And they do. Being able to interact with them is a gift.”

“It’s nice to talk to students and fellows, tell them this is the future, and wonder how much further they’re going to take it.”