Immunotherapy shows promise for type 1 diabetes
An investigational immunotherapy with proinsulin C19-A3 peptide injection is safe without adversely affecting β cell function and stabilizes daily insulin use in patients with new-onset type 1 diabetes, a study has shown.
The proinsulin C19-A3 peptide represents an immunodominant region of the human leukocyte antigen (HLA)-DR4(DRB1*0401)-restricted proinsulin peptide, an autoantigen associated with type 1 diabetes.
“When someone is diagnosed with type 1 diabetes they still typically have between 15 percent and 20 percent of their β cells. We wanted to see if we could protect these remaining cells by retraining the immune system to stop attacking them,” said study principal investigator Professor Mark Peakman of King’s College London, UK.
The multicentre double-blind phase Ib trial involved 24 adults (aged 18–45 years) with HLA-DRB1*0401 genotype, >0.2 nM stimulated C-peptide on MMTT#, and tested positive for one out of three islet autoantibodies (GAD, IA-2, or ZnT8) ##. Within 100 days of being diagnosed with type 1 diabetes, they were randomized to one of the three arms: high-frequency (C19-A3 10 µg Q2W) or low-frequency (C19-A3 10 µg Q4W alternating with saline Q4W) immunotherapy, or placebo (saline Q2W) by intradermal injection over 6 months, for a total of 12 injections.
During the treatment course, peptide injection was well tolerated with no serious treatment-emergent adverse events and hypersensitivity reactions. [Sci Transl Med 2017;doi:10.1126/scitranslmed.aaf7779]
Compared with a 50 percent increase in daily insulin use in the placebo arm, the need for insulin remained unchanged in both immunotherapy arms over 12 months (p=0.01).
“It was encouraging to see that people who receive the treatment needed less insulin to control their blood glucose levels, suggesting that their pancreas was working better,” said coprincipal investigator Professor Colin Dayan from Cardiff University, UK.
According to the authors, accelerated loss of C-peptide secretion is an indicator of elevated β cell damage. They found that both immunotherapy arms better preserved the levels of stimulated C-peptide, showing less percentage change in loss of C-peptide from baseline through 9 months in contrast to the placebo group, which showed a significant C-peptide loss from baseline as early as 3 months from diagnosis (p=0.03 vs high-frequency peptide arm).
In the immunotherapy groups, C-peptide retention was associated with significantly higher interleukin (IL)-10 responses to proinsulin stimulation compared with placebo (p=0.015 and p=0.003 for high- and low-frequency peptide groups, respectively).
In addition, responders to the immunotherapy groups showed an increased FoxP3 expression in regulatory T cells compared with nonresponders (p=0.05). Proinsulin/C-peptide ratio, an indicator of β cell stress, was also significantly higher in nonresponders compared with responders to immunotherapy at multiple timepoints from baseline.
These findings indicate that a key therapeutic mechanism of C19-A3 peptide administration may be through the induction of IL-10 responses involved in regulating inflammation, which could otherwise lead to an autoimmunological attack on the β islet cells, the authors suggested.
“We still have a long way to go, but these early results suggest we are heading in the right direction. The peptide technology used in our trial not only appears to be safe for patients at this stage, but it also has a noticeable effect on the immune system,” said Peakman.