Peptide immunotherapy to stop new-onset type 1 diabetes
by Adam Burrack, PhD
The recent observation that so-called hybrid peptides may represent new targets of the immune system which are targeted in the build-up to developing type 1 diabetes has opened new vistas of possibilities for trying to re-establish immune tolerance to pancreatic beta cells. This paradigm-shifting observation may answer the long-standing conundrum of ‘why are beta cells specifically targeted’? If a ‘new’ target (as far as the immune system is concerned, if the target was not shown to T cells in the thymus, then if it is found in the periphery it’s new) is associated with (1) inflammation and (2) dead cells, the immune system will interpret these signals as a call to action to clear an infection. Hybrid peptides produced from dead and dying beta cells fit these two criteria. Viewed from this lens, the immune system is logically attacking beta cells.
The question for basic researchers and clinicians was how to leverage this knowledge to try to prevent or stop type 1 diabetes development in at-risk human patients. Whom do you treat? With which potential hybrid peptide? For how long? What do you measure to track efficacy of treatments?
In a report recently published in Science Translational Medicine, researchers attempt to leverage this new knowledge in a phase 1 (ie, safety) clinical trial to stop new-onset type 1 diabetes in human patients. Several clinical research groups were involved in this work, including Universities and Hospitals in Cardiff (Cardiff School of Medicine), London (King’s College), Newcastle-upon-Thyne, University of Swansea, and biostatisticians at Western Michigan University. This paper has >20 authors, representing a ton of work by many different people at different institutions. This type of large collaborative effort is a good example of how successful, impactful, clinical trials must be conducted.
Some answers to several of the above questions were developed. As with all good research, more questions were raised. Firstly, researchers treated new-onset type 1 diabetic patients, within 100 days of diabetes onset. These subjects were well within the ‘honeymoon’ phase of the disease, meaning they had residual C-peptide production: this is indicative of moderate to significant remaining beta cell mass. Therefore, if a treatment could stop beta cell destruction in these individuals, it might facilitate diabetes reversal. This treatment was not intended to reverse long-term diabetes or replace lost beta cell mass. The goal was to preserve residual beta cell mass in new-onset type 1 diabetic patients.
Second, the researchers went after the most logical target hybrid peptide; proinsulin. As a reminder, insulin is made as an inactive precursor within beta cells, preproinsulin. Various portions of this protein are cleaved (cut off) within beta cells before the active hormone, insulin, is released. The final portion of proinsulin cut off is called C-peptide (for its shape) and can be measured in the circulation. In fact, C-peptide level is one way to measure small amounts of insulin production by remaining beta cells in long-term type 1 diabetic patients. One of the hybrid peptides recently characterized contains portions of C-peptide and portions of the insulin protein. Therefore, to try to re-establish tolerance to this hybrid peptide, or other pro-insulin-derived peptides, patients were treated with pro-insulin. Other recently-characterized targets of autoreactive T cells map to a different portion of the proinsulin molecule. Therefore, proinsulin is a good choice for initial attempts to try to re-establish tolerance to beta cells.
Long story short, these results show promise – this is why it’s a Science Translational Medicine publication. Some individuals responded to the treatment more effectively than others, for reasons which are not fully understood. For responders, the treatment appeared to maintain beta cell mass – as shown by preserved C-peptide levels – and may have promoted the activity of regulatory T cells (though this was not conclusively shown by this study). As I’ve discussed before, regulatory T cells are a key cell type which typically protects our own tissues from attack by the immune system. Adding back these cells in large numbers is a separate potential approach to re-establish tolerance to pancreatic beta cells and reverse type 1 diabetes. These two outcomes, preserving beta cell mass and promoting regulatory T cells, are a great starting point for a new clinical therapy.
Despite these promising early returns for peptide immunotherapy (PIT) in individuals with new-onset T1D, this was only a phase 1 clinical trial and several critical questions remain. First and foremost, this study demonstrated that the ‘honeymoon phase’ was prolonged, not that the T1D disease process was halted. Future phase 2 or phase 3 studies, conducted over longer time frames, will presumably address these questions. Second, while this report suggests enhancement in regulatory T cells, it does not demonstrate insulin (or proinsulin)-specific regulatory T cells, which are the most likely to help protect beta cells. As we have previously described in this series, adding back regulatory T cells specific to insulin peptides is a separate strategy which may synergize with the PIT approach. Presumably phase 2 or 3 trials would more specifically address regulatory T cells. Having stated these limitations, this phase 1 trial is a very promising result, in a high-tier journal, and many researchers (in particular in my sub-field) will be highly anticipating phase 2 results of this and similar studies in the USA. This is a great start toward re-establishing insulin-specific immune system tolerance in new-onset type 1 diabetic individuals.
The full-length manuscript can be accessed here.