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A pilot clinical trial in the US has found a new immunotherapy treatment to be safe in people with new onset type 1 diabetes (T1D).

After clinical presentation of T1D, beta cell loss continues progressively in most people until C-peptide levels, a marker of endogenous insulin production, is absent or present in very low levels. Despite intensive research efforts for more than 20 years, no therapy is currently available to prevent beta cell loss in T1D.

The major focus in recent years has been to develop safe and effective immunotherapies that re-train the immune system to prevent it from targeting beta cells. In particular, short immunogenic peptides have been shown to restore immune tolerance in preclinical animal models of T1D, and have been successful in reducing severity of symptoms for many allergy sufferers.

The purpose of this trial, published in Science Translational Medicine was primarily to assess the safety of the peptide proinsulin C19-A3, an immunodominant region of proinsulin presented by the complex encoded by HLA-DR4 (DRB1*0401). This peptide has previously been shown to modulate T helper cells in patients with long standing type 1 diabetes that were HLA DRB1*0401 positive. Only a small proportion of people with T1D carry this allele. 27 adults within 100 days of diagnosis were split into 3 groups: two groups were given the treatment via intradermal injection every two weeks, or every four weeks, while the final group received a placebo. The trial lasted for 6 months and participants were closely monitored for adverse events while insulin production and T cell activity was also measured.

While this study was not adequately powered to show statistical significance between groups, the team assessed significance compared to baseline within groups. Compared to baseline,  participants who received the placebo showed a significant decline in stimulated AUC C-peptide at 3, 6, 9, and 12 months, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. Daily insulin use in the placebo group increased by 50% over 12 months but remained unchanged in both intervention groups. C-peptide retention in treated participants was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell–specific CD8 T cells, and favourable β cell stress marker (proinsulin/C-peptide ratio).

The results indicate that this therapy is safe for people who are HLA-DR4 (DRB1*0401) positive. Larger clinical trials are now needed to establish how effective the treatment is in preserving beta cell function and insulin production, and if the approach would be safe and effective in children as well as adults. Further trials will also determine whether the approach could be modified to apply to a broader population of people with T1D.

If developed into a treatment, this could mean reduced risk of complications due to preservation of beta cell function for longer in those that are newly diagnosed. It is also a step towards a preventative treatment of T1D.

In Australia, a team at UQ Diamantina Institute led by Prof Ranjeny Thomas are completing preclinical studies on an immunotherapy using nanoparticles to target immune cells. T1DCRN Career Development Award recipient A/Prof Anandwardhan Hardikar and his team are investigating biomarkers of beta cell loss and function, which will work hand in hand with immunotherapies to assess effectiveness with the intent to prevent or delay diagnosis of T1D and further beta cell loss after diagnosis.

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