Low-dose interleukin-2 safe and effective in treating immune-mediated diseases

By Todd Neale, Senior Staff Writer, MedPage Today:
Published: November 30, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner   
Action Points 
Low-dose interleukin-2 immunotherapy appears to be safe and effective in treating two immune-mediated diseases, hepatitis C virus (HCV)-induced vasculitis and chronic graft-versus-host disease (GVHD).


Interleukin-2 increased the proportion of regulatory T cells (Tregs) in patients with hepatitis C virus (HCV)-induced vasculitis and in those with chronic graft-versus-host disease.
Low-dose interleukin-2 immunotherapy appears to be safe and effective in treating two immune-mediated diseases, two small, uncontrolled studies showed.

In the first study, David Klatzmann, MD, PhD, of Pierre and Marie Curie University in Paris, and colleagues found that interleukin-2 increased the proportion of regulatory T cells (Tregs) in all 10 patients with hepatitis C virus (HCV)-induced vasculitis and improved symptoms of vasculitis in eight, with few side effects.

In the second study, John Koreth, MBBS, DPhil, of the Dana-Farber Cancer Institute in Boston, and colleagues found that the treatment induced partial responses in about half of patients with chronic graft-versus-host disease (GVHD), with no cases of relapse or progression of the disease.

The results of both studies -- which were reported in the Dec. 1 issue of the New England Journal of Medicine -- "signal a major shift in the therapeutic use of interleukin-2," according to Jeffrey Bluestone, PhD, of the University of California San Francisco.

Overall, the treatment appeared to be safe, but the long-term effects are uncertain, he wrote in an accompanying editorial.

"Thus, these articles and others have provided a path forward for the effective use of interleukin-2 as a regulatory immunotherapy," he concluded. "Future trials involving larger numbers of patients and appropriate control groups are needed to determine the efficacy of not only interleukin-2 therapy but also other approaches to improving Treg numbers and function in autoimmune diseases and GVHD and inhibiting them in cancer."

Klatzmann and colleagues examined whether interleukin-2 could be used to treat patients with vasculitis induced by HCV that does not respond to standard antiviral therapy, rituximab (Rituxan), or both. Interleukin-2 is approved for use as an adjunctive treatment for renal cell carcinoma. It promotes survival and function of Treg cells, which inhibit immune responses.

The study included 10 patients with mixed cryoglobulinemic vasculitis who were not receiving glucocorticoid or immunosuppressant therapy (median age 58.5).

The patients received one course of interleukin-2 at 1.5 million IU per day for five days, followed by three five-day courses of 3 million IU/day at weeks three, six, and nine.

By week nine, there was a significant increase in the proportion of CD4+ T cells that were Tregs -- from 3.6% to 11.8% (P=0.004). That improvement met the primary endpoint of at least a 4% absolute increase.

Nine of the 10 patients also had a reduction in cryoglobulinemia, eight patients saw an improvement in vasculitis, and there was an overall reduction in the expression of genes related to inflammation and oxidative stress.

The treatment appeared to be safe, with no adverse events higher than grade 1 and no significant changes in circulating levels of granulocytes, red cells, or liver enzymes.

In addition, the treatment did not increase the numbers of effector T cells or induce vasculitis flare or increased HCV viremia.

"Further studies are needed to determine whether this intervention could be further modified and whether it would also be effective in the treatment of other inflammatory and autoimmune diseases, such as atherosclerosis or type 1 diabetes," Klatzmann and colleagues concluded.

Koreth and colleagues evaluated interleukin-2 as a treatment option for patients with chronic GVHD, which develops in more than half of patients who have undergone allogeneic hematopoietic stem cell transplantation.

The study included 29 patients (median age 49.5) whose disease did not respond to systemic glucocorticoid therapy.

For eight weeks, patients received daily, low-dose subcutaneous interleukin-2 -- escalating from 300,000 IU per square meter of body-surface area to 1 million IU, then to 3 million IU, if tolerated. The highest dose, however, ...
resulted in unacceptable constitutional symptoms, including fever, malaise, and arthralgia, so the maximum tolerated dose was 1 million IU.

None of the patients had a relapse or progression of chronic GVHD, clinical flares, or relapses of an underlying hematologic cancer.

Numbers of CD4+ Treg cells increased in all patients, although of the 23 who could be evaluated for a clinical response, 12 had a partial response involving multiple sites and 11 had stable disease.

The peak median number of CD4+ Treg cells at four weeks was more than eight times higher than at baseline (P<0.001), without any change in the conventional T cells.

For patients who continued to receive interleukin-2 beyond the initial treatment period, the immunologic and clinical response was sustained and the glucocorticoid dose could be tapered by an average of 60%.

The researchers said that the treatment had an acceptable side-effect profile. It did not induce significant leukopenia, neutropenia, thrombocytopenia, or hepatic dysfunction.

Two patients developed grade 4 thrombotic microangiopathy-associated renal failure requiring dialysis, but they were also taking sirolimus (Rapamune) plus tacrolimus.

Other adverse events included major infections in three patients, reversible grade 3 injection-site induration in three, grade 2 constitutional symptoms in one, grade 2 renal dysfunction in one, and grade 2 thrombocytopenia in one.