Immunotherapy for Type 1 Diabetes Safe, Promising in Small Study

Ricki Lewis, PhD

August 10, 2017

Proinsulin peptide immunotherapy, used much like allergy desensitization, is safe and shows signs of dampening autoimmunity in patients with newly diagnosed type 1 diabetes, according to results of a study published online August 9 in Science Translational Medicine.

Immune-mediated loss of beta-cell mass and function continues after diagnosis in most patients with type 1 diabetes. Researchers have proposed using immunotherapy to quell underlying autoimmunity by awakening or restoring regulatory T cells.

One way to do that is with antigen-specific immunotherapy. The strategy introduces short peptides that are part of the epitopes of major autoantigens. This approach, called peptide immunotherapy (PIT), is being tested to treat allergies and autoimmune inflammatory conditions such as multiple sclerosis and celiac disease.

In a study published in 2009, Mark Peakman, MBBS, PhD, professor of clinical immunology at King's College London, United Kingdom, and colleagues administered a peptide from an immunodominant region of proinsulin to patients who had had type 1 diabetes for years (Clin Exp Immunol. 20090;155:156–165). The goal was to modulate the activity of autoreactive CD4 T cells and detect insulin production from circulating C-peptide, which is split from proinsulin as insulin is released. However, in this patient group, with long-standing disease, beta-cell destruction was too advanced to detect C-peptide, and thus the efficacy of the approach could not be measured.

Therefore, in the current study, Mohammad Alhadj Ali, MD, PhD, clinical research fellow in diabetes and endocrinology at Cardiff University School of Medicine, Wales, and colleagues evaluated PIT in patients with newly diagnosed T1D who had detectable levels of circulating C-peptide.

The researchers randomly assigned the 27 participants who met the criteria (diagnosed within the past 100 days and with autoantibodies) to a high-frequency group (10-mg proinsulin C19-A3 peptide injected intradermally every 2 weeks), a low-frequency group (10-mg every 4 weeks alternating with saline every 4 weeks), or placebo (saline injections every 2 weeks). They evaluated residual C-peptide at baseline and at 3, 6, 9, and 12 months thereafter.

Patients treated with placebo experienced a significant decline in stimulated C-peptide levels at all points, whereas those in the PIT arms did not. Moreover, patients in the PIT group did not have a significant increase in daily insulin use over the yearlong study, compared with a 50% increase in daily insulin use among those in the placebo group.

Importantly, the treatment did not appear to cause hypersensitivity or accelerate loss of beta-cell function.

In addition, the immunological signs were promising. A subset of participants called C-peptide responders, defined as those who reached 100% or more of the baseline value of C-peptide over the 6-month treatment period, had higher levels of interleukin-10, decreasing levels of interferon gamma against proinsulin, and increased FoxP3 expression, all of which suggest the regulatory T cells are being revved up to counter the autoimmunity.

In addition, proinsulin/C-peptide ratios did not change significantly among C-peptide responders compared with baseline, reflecting less beta-cell stress. In contrast, nonresponders showed an increase in the proinsulin/C-peptide ratio at multiple points, relative to baseline.

"Our data can be interpreted as indicating that peptide-treated C-peptide responders have less beta-cell stress compared with nonresponders," the authors write.

Of 10 responders, three were in the high-frequency group, six in the low-frequency group, and one in the placebo group. The researchers call the case of the placebo responder "intriguing" and suggest that further observational studies may reveal other "nonprogressors" and perhaps could reveal what they share.

Limitations of the study include the small number of participants, variability of C-peptide measurements, and insufficient power to discern relative efficacy between the two treatment groups.

"Next steps will be bigger trials to test whether the therapy can halt beta-cell damage. We need efficacy data—a phase 2 study will probably start in 2018. We need to work out whether the treatment needs to be continuous or periodic. It may need to be given for several months initially, followed by repeated courses," said study leader Dr Peakman in an interview with Medscape Medical News.

He's looking ahead. "We don't think this therapy will make people insulin-independent if it is given at diagnosis — there's probably too much loss of function. But it could be considered in prevention in the future, such as in healthy subjects at high risk of future diabetes — that is why the safety profile is important. The more beta cells you can keep, the better the diabetes is controlled and that gives fewer complications." The group plans to study children in the future, he added.

"It's an encouraging report, but unconvincing," Kenneth McCormick, MD, director, division of pediatric endocrinology at Children's of Alabama, Birmingham, told Medscape Medical News, noting differences among the groups. "The placebo group at baseline required higher insulin doses and had more elevated glycated hemoglobin, there was significant overlap in data among the groups, and there's a significant difference between the initial insulin dose per kilogram between adults and children."

Dr Peakman is an inventor on a patent issued to King's College London that covers peptides relevant to T1D immunotherapy. He has consulted with UCB Pharma for a phase 2 study design to test the immunotherapy. Disclosures for the coauthors are listed in the paper.

Sci Transl Med.  Published online August 9, 2017. Article

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