Study illuminates biology behind promising therapy for graft-versus-host disease
Researchers see implications for treatment of other immune system-related disorders
Dana-Farber Cancer Institute researchers have traced the biological backstory of one of the most improbable-sounding discoveries of recent years: that an immune system stimulant can actually suppress the immune system activity responsible for a common complication of donor stem cell transplants in cancer patients.
In a study published in the journal Science Translational Medicine, the researchers detail how low doses of the drug interleukin-2 (IL-2) can alleviate chronic graft-versus-host disease (GVHD), a debilitating condition that often occurs in patients who have received a stem cell transplant. In patients with chronic GVHD, donor immune cells launch an attack on healthy tissue. IL-2 is so versatile at restoring immune system balance, the researchers found, that it may eventually become a primary treatment for chronic GVHD and may even hold promise for treating autoimmune diseases, such as rheumatoid arthritis and lupus, which result from a misguided immune system attack on otherwise healthy organs and tissues.
"We found that low doses of IL-2 work through several independent mechanisms to restrain the aggressive immune response that can lead to chronic GVHD," said John Koreth, MBBS, DPhil, who co-led the study with Dana-Farber colleagues Ken-ichi Matsuoka, MD, PhD, and Haesook Kim, PhD. "The effect of low-dose IL-2 is so robust that it may have application for a variety of conditions associated with an overactive immune system."
The new study grew out of a much-discussed paper from 2011. In a phase I clinical trial, Koreth and his colleagues found that half of patients with chronic GVHD experienced a marked improvement in symptoms after receiving daily, low-dose injections of IL-2. The finding may well have caused double takes across the cancer research world. "Because of its ability to stimulate the immune system, IL-2 was previously approved by the Food and Drug Administration for the treatment of advanced melanoma and renal cell cancer," said Robert Soiffer, MD, of Dana-Farber, a co-author of the new study. "Since IL-2 is an immune system stimulant – revving up the immune system's attack on tissue – it might initially have been expected to exacerbate GVHD, not relieve it."
The key was in the low doses used. "At high doses, IL-2 activates a wide range of immune system cells – 'effector' T cells, which lead the attack on disease, and 'regulatory' T cells that dial back the attack after it's finished," explained Dana-Farber's Jerome Ritz, MD, the study's senior author. "We knew that regulatory T cells [or T-regs] have a high affinity for IL-2 – meaning they bind especially well to the drug at low concentrations. We theorized that at low doses, IL-2 would activate T-regs to a far greater extent than conventional effector T cells [or Tcons], thereby reducing the immune response that gives rise to chronic GVHD."
In the new study, the investigators found that not only was their theory correct, but IL-2's ability to boost T-reg levels was more far-reaching than they had thought.
By tracking T cell levels in patients participating in the phase I trial, the researchers discovered that IL-2 was spurring T-reg activity through three distinct mechanisms. "It caused the T-regs that were initially there to proliferate, as we expected, but its effects went beyond that," Ritz remarked. "We found that the thymus gland, which usually shrinks in adults, was actually producing more fresh T-regs. Because these cells are newer and younger, they can exert broad control over an overactive immune system." The researchers also found that IL-2 enabled T-reg cells to live longer, increasing the time that they could rein in the immune system.
"We found that after eight weeks of IL-2 therapy, there was a five- to six-fold increase in the number of T-reg cells in these patients," Koreth remarked. That increase returned the immune system to a condition of "homeostasis," the delicate balance between T-regs and T-cons that enables the immune system to effectively fight disease without aggressively attacking normal tissue.
"We found that the T-reg numbers increase rapidly during the first weeks of IL-2 therapy and plateau after that, maintaining homeostasis for prolonged periods," Koreth noted.
The results of the study have encouraged investigators to open a new clinical trial to explore whether IL-2 can be effective earlier in the course of treatment for chronic GVHD. (Patients in the original clinical trial had chronic GVHD for about two years before starting IL-2 therapy. The new trial will administer the drug to patients earlier in the course of their disease.)
"Our findings also raise the possibility that low-dose IL-2 might help people with autoimmune diseases, which are also characterized by a deficiency of T reg cells," said Ritz. "The ability to increase the concentration of T regs may be useful in a variety of settings."
Co-authors of the study include Gregory Bascug, Sean McDonough, Yutaka Kawano, MD, PhD, Kazuyuki Murase, MD, PhD, Corey Cutler, MD, Vincent Ho, MD, Edwin Alyea, MD, Philippe Armand, MD, Joseph Antin, MD, and Robert Soiffer, MD, of Dana-Farber; and Bruce Blazar, MD, of the University of Minnesota.
Funding for the study was provided by grants from the National Institutes of Health (AI29530 and CA142106), the Jock and Bunny Adams Research and Education Endowment, and the Ted and Eileen Pasquarello Research Fund, with support from the Dana-Farber Dunkin' Donuts Rising Stars program, and the American Society of Blood and Marrow Transplantation/Pharmion.
At Dana-Farber/Brigham and Women's Cancer Center, stem cell transplants are performed in the Stem Cell Transplantation Program.