Personalising type 1 diabetes immunotherapy
Immunotherapy offers new hope to those at risk of type 1 diabetes, with teplizumab being the first approved treatment. Research into identifying those most likely to respond to immunotherapy and which treatment might work best was reviewed at the recent Advanced Technology & Treatments for Diabetes (ATTD) conference. Dr Susan Aldridge reports.
Teplizumab is an anti-CD3 antibody that can delay or prevent the onset of clinical diabetes in those at risk, buying them valuable time free of hyperglycaemia. Many other potential immunotherapy treatments are under investigation, which will offer choice to those eligible. People vary in their response to immunotherapy and some may respond better to one treatment than another – the latest research is monitoring these responses to type 1 immunotherapies by tracking biomarkers.
Dr Laura Jacobsen, paediatric endocrinologist at the University of Florida, said: “Now is the time to be identifying and validating these biomarkers, so that as we move forward with screening and prevention approaches, we have evidence behind them.” She cited the case history of ‘Sam’, a 15-year-old boy diagnosed with type 1 diabetes just a week ago and at the clinic for an appointment. There would be the usual discussion of daily diabetes care, mental health and diabetes technology – pump, continuous glucose monitoring and closed loop. And what about tailored immunotherapy to preserve his beta cells? “What I envisage in the future is that during this early onset period, we can use the opportunity to discuss immune therapies or cell therapies that can help prolong the C-peptide or beta cell mass that is present during this critical time period,” said Dr Jacobsen. “We are on a journey towards personalised medicine in type 1 diabetes.”
Monitoring C-peptide response
Teplizumab is not the only player in the field of type 1 diabetes immunotherapy. Clinical trials have shown that a range of different immunotherapies can interrupt C-peptide loss and by multiple mechanisms with different targets. Immunotherapies and their safety profiles are also well established for use in other conditions. “We’ve been doing immunotherapy clinical trials in type 1 diabetes for over 35 years, but there are still a lot of challenges in getting them to people with diabetes,” said Dr Jacobsen. One of the main challenges is the heterogeneity of type 1 diabetes and the fact that it’s not always clear what is actually going on with the beta cells that need to be preserved. These factors may affect an individual’s response to a particular immunotherapy. The response needs to be measured with peripheral blood biomarkers, which is hard when looking at a condition that actually occurs in an organ – the pancreas – in the centre of the body.
These biomarkers are particularly important in type 1 diabetes because there is a critical period of time before permanent beta cell damage occurs. “If we adopt a trial-and-error approach to immunotherapy, we will miss out on this window of opportunity,” said Dr Jacobsen. “One way forward would be to use a biomarker at the start to see which antibody to use to increase the odds of success. Measurement of a biomarker can be done at the start and during the course of the treatment to monitor response.”
One obvious biomarker is C-peptide and a clinical responder to immunotherapy has so far been defined mostly in the context of clinical trials that measure the amount of C-peptide over time. The bigger the gap between the observed C-peptide on the immunotherapy and that observed on placebo, the more likely it is that the individual is responding.
This approach was used in trials of six different immunotherapies that were directed towards either B-cells (rituximab) or T-cells (abatacept, alefacept, teplizumab and high- and low-dose anti-thymocyte globulin – ATG). They all showed a group of individuals who responded better than others. Analysis of this data showed that age was a key factor in response to these different immunotherapies. Younger individuals responded better to teplizumab, abatacept and rituximab, while older individuals did better with ATG. People at risk could one day be assigned to an immunotherapy on the basis of their age.
Biomarkers and genetic signatures
The mechanism of action of an immunotherapeutic could also produce a telltale biomarker. For instance, abatacept prevents the activation of T-cells – if it is working, there will be a lot of immature T-cells around in that individual and that is seen among responders. “That’s a pretty easy biomarker to look at going forward,” said Dr Jacobsen. On the other hand, some immunotherapies act by overstimulating T-cells, leaving a ‘signature’ of exhausted T-cells. This has been found in those who benefited most from low-dose ATG, teplizumab and alefacept.
Finally, T-cell directed therapies affect other cell types, such as neutrophils. This leads to the upregulation of neutrophil genes in abatacept and low-dose ATG responders. “It’s also interesting to note that exhausted T-cells and increased neutrophil gene expression are seen in the natural history of type 1 diabetes to be associated with lower C-peptide decline,” said Dr Jacobsen. “Maybe immunotherapy can push people into that more favourable environment.”
Monitoring someone’s response to immunotherapy is still wasting precious time if they turn out to be a poor responder and must try another therapy. Age is one factor that may set an individual on the right immunotherapeutic path, but the latest research shows that there is also a link between response and the possession of certain genetic variants, which can be screened for before the start of immunotherapy. For example, a post-hoc analysis of teplizumab shows that participants who were HLA-DR3-negative, HLA-DR4-positive or anti-zinc transporter 8 antibody-negative had a better chance of responding to teplizumab.
There have been similar studies on other genetic markers of response. Given the increased ease and lower cost of genetic screening, this approach could be used to direct those at risk towards the immunotherapy that would give them the best chance of a response and more years free of hyperglycaemia and complications – and perhaps escaping type 1 diabetes altogether. “These are very encouraging early findings,” concluded Dr Jacobsen. “The goal is to find what therapy fits best for ‘Sam’ – and we’re almost there, but not quite.”
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.