Ashish Marwaha, BMBCh, MA(Oxon), Ph.D.
Department of Genetics, University of Toronto, Toronto, Canada & Department of Dermatology and Skin Science, The university of British Columbia, Vancouver, Canada
Anne Pesenacker, Ph.D.
Department of Surgery, The University of British Columbia, and Child & Family Research Institute, Vancouver, Canada & Division of Infection and Immunity, Institute of Immunity & Transplantation, University College London, London, UK
Type 1 diabetes (T1D) is caused by T-cell-mediated destruction of pancreatic beta cells. It is likely that blockade of pathogenic T-cells in individuals with recent-onset T1D would halt the destruction of beta cells and may allow restoration of endogenous insulin secretion. Ustekinumab inhibits IL-12/23 p40 and thereby limits the function of IL-17 and/or IFN-γ secreting T-cells, both of which have been implicated in the pathogenesis of T1D.
In 2016-2017, a phase IIa trial was undertaken to test the safety of ustekinumab administration to 20 young adults (18-25yrs) with recent-onset T1D. Biomarker assays were used to measure immune cell populations before and after treatment revealing a dose-dependent increase in the frequency of memory regulatory T-cells (p<0.01), changes in the Treg signature, and a reduction in the frequency of IL-17+IFN-γ+ Th17.1-cells (p<0.05). Moreover, patients treated with 90mg of ustekinumab had a higher clinical response compared to those treated with 45mg. Results from this trial indicated that changes in immune cell populations may predict a clinical response to ustekinumab therapy.
Two randomized, placebo-controlled clinical trials to test the efficacy of ustekinumab in new-onset T1D are planned in Canada and the UK. We have harmonized sample collection timing, processing and storage conditions, and undertook a cross-lab training process to standardize a series of bioassays to measure the effects of ustekinumab on different T-cell populations. By using standardized assays we will increase the statistical power of these independent trials and provide a platform for adoption of harmonized biomarkers in future immunotherapy trials in T1D.