Objective
We will carry out mechanistic studies on two trials of ustekinumab in T1D. Laboratories in the UK and Canada will share methods and approaches and agree on a common set of protocols and assays so that we can combine data from both studies. This will first increase the possibility of finding a biomarker of response to therapy and second test a new model for harmonizing the way biological outcomes are measured in the lab.
Background Rationale
Previous studies in animal models and in individuals with T1D have shown that two types of immune T cells work together to destroy insulin-producing pancreatic beta cells. Currently, a drug (ustekinumab) exists that is known to block the activation of these two T cell types is currently licensed for the treatment of psoriasis and Crohn’s disease, where it has proven to be both safe and effective. Here will test the effects of ustekinumab in subjects with recent onset T1D in two clinical trials: one in children (12-18) in the UK; and one in Canada in youg adults (18-25). To increase the power of both studies we propose to harmonize the methods we use to measure the biological responses to this therapy. By harmonizing our methods we have a greater chance of finding biomarkers that can either predict and/or monitor the response to therapy. .
Description of Project
In type 1 diabetes (T1D), cells from the immune system called T cells attack and destroy insulin-producing beta cells leaving affected individuals with a lifelong dependence on insulin. Even with insulin injections, blood glucose control is imperfect, leading to an increased risk of complications from chronic hyperglycemia and a shortened life span. In preliminary work, we have demonstrated that a biologic drug (an antibody known as ustekinumab) that inhibits inflammation can be safely administered to young adults with new onset diabetes.
Two multi-centre clinical trials have been recently funded to test the ability of ustekinumab to halt the progression of T1D in children or young adults with recent onset T1D. 72 children aged 12-18 or 66 young adults aged 18-25 with new onset (within 100 days of being diagnosed) T1D. The trials are called USTEKID and USTID2, respectively. In our first study we found that this drug can decrease inflammatory proteins, specifically IFN-gamma and IL-17, that are thought to damage islets. Thus following changes in these inflammatory proteins, as well as changes in the balance of immunoregulatory versus inflammatory cells may lead to insight into the drug's mechanism of action as well as biomarkers of response to therapy. To comprehensively evaluate biomarkers of response and mechanism we propose to harmonize the mechanistic studies being carried out in both clinical trials. Specifically, for both USTEKID and UST1D2 we will collect blood at similar time points post therapy and carry out the same biological assays. By working together we will increase the available sample size thereby more rapidly identifying whether or not this is an effective therapy for T1D. Overall our proposal will contribute towards the study of how effectively ustekinumab can improve the outcomes for individuals with recent onset T1D.
Beyond directly contributing to the clinical research in T1D, this study represents a new model of international collaboration. By working together we have the opportunity to increase the rigour and reproducibility of our biomarker assays as well as to create a new collaborative model for evaluating outcomes from international, multi-centre clinical trials.
Anticipated Outcome
We predict that we will find biomarkers that can identify which patients are most likely to respond to ustekinumab pre-treatment, as well as biomarkers that reveal which patients respond favorably to the drug once they begin taking it. In the future, these data will help us to select which patients to treat with ustekinumab as well as to develop new ways to follow how the drug restores an appropriate immune balance once a patient begins taking the drug.
Relevance to T1D
This project is highly relevant to T1D as aims to develop biomarkers to predict and monitor responses to a drug therapy that may preserve beta cell function and insulin secretion. .