DF/HCC Researchers Reinvent Anti-tumor IL-2 Therapy for GVHD
Graft-versus-host disease (GVHD) often occurs after an allogeneic hematopoietic stem cell transplant (HSCT) from a healthy donor is given to treat hematological cancers. The donor’s stem cell graft replaces the recipient’s immune system, which had tolerated cancer cells, with a normal system that now kills them. In many recipients, however, the new immune system also attacks healthy cells. This response can lead to chronic GVHD, an inflammatory immune reaction associated with substantial morbidity and mortality and with clinical manifestation similar to autoimmune diseases such as systemic lupus erythematosus or scleroderma. Steroid treatment is effective in some patients, but about 50 percent of patients suffer debilitating chronic GVHD, and there is no established second-line treatment. Further, incidences of chronic GVHD have increased with the international bone marrow registry’s successes in finding more suitable volunteer donors for cancer patients requiring stem cell transplants. Thus, developing innovative strategies to prevent or treat GVHD is a major unmet need.
A recent phase I trial led by DFCI’s John Koreth, MBBS, DPhil, Robert Soiffer, MD, and Jerome Ritz, MD found that low-dose interleukin 2 (IL-2) therapy improved symptoms in 15 of 23 participants with severe, long-standing chronic GVHD. Participants had previously failed several treatments, including steroids, and had significant tissue damage and scarring. They self-administered IL-2 by daily injections for 8 weeks, followed by 4 weeks off. GVHD did not worsen, and leukemia did not recur in any patient. Remarkably, regulatory T cells (Treg), which help suppress excessive immune responses, increased dramatically in every patient. This initial study, published in a December 2011 NEJM, established the immunologically effective dose of IL-2 that can be safely administered to chronic GVHD patients.
DF/HCC researchers have opened a phase II trial to assess the efficacy of low-dose IL-2 over a longer term (12 weeks). It will also assess whether starting the therapy earlier in the disease progression, when patients have less tissue damage, provides more benefit. Primary objectives are to measure the overall response rate. Secondary objectives include determining toxicity, overall survival, and immunological effects over a 3-year time frame. Led by Koreth, this trial plans to accrue 31 participants with either limited or extensive chronic GVHD despite using steroids for at least 4 weeks. Participants will continue taking steroids with IL-2. Those who respond to IL-2 may continue receiving the therapy after the initial trial period.
Decreased Regulatory T Cells in GVHD
The rationale for both of these trials stems from Ritz’s studies of GVHD patients following allogeneic HSCT. In a 2005 study published in Blood, his lab discovered that GVHD patients had reduced numbers of Treg cells, which had been recently identified as key suppressors of the immune response. The decrease in regulatory T cells helped explain why the donor immune system could not become tolerant to normal tissues in some patients.
IL-2 was initially identified as a T cell growth factor and was being used to try to stimulate anti-tumor T cells in cancer patients, usually with disappointing results. “Once we knew about Treg, in 2006 we examined blood samples of cancer patients who had received IL-2 in the 1990s and discovered they had an expansion of Treg cells,” recalls Ritz, who is also the Executive Director of the DF/HCC Cell Manipulation Core Facility. He reasoned that this expansion, which would have increased tolerance, counteracted an anti-tumor response and may help explain the low success rate of IL-2 as a cancer treatment. The Treg expansion also suggested a completely new type of therapy. Instead of using IL-2 to stimulate T effector cells to increase anti-tumor response in cancer patients, he decided to do the opposite and use it to suppress the immune response that promotes GVHD. Theoretically, this novel approach might also alleviate autoimmune inflammation in non-cancer patients.
Because Treg cells have a high affinity receptor for IL-2, Ritz hypothesized that “a little would go a long way,” so the phase I trial only tested low doses of IL-2. If the new trial succeeds, the researchers want to determine how soon after transplant to give the therapy, how long to continue it, and whether it increases the long-term risk of cancer or infection. “We didn’t see that in the first trial,” says Koreth, “so we hope that IL-2 used in this fashion will not have serious toxicities.”
Phase II Trial
Title: Daily IL-2 for Steroid-Refractory Chronic Graft-versus-Host-Disease
John Koreth, MBBS, DPhil (DFCI)
The trial is open and accruing. For information on ClinicalTrials.gov, go to NCT01366092.