Postdoc Benaroya Research Institute Seattle, Washington, United States
Abstract Text: Tregs are critical for peripheral immune tolerance, and defects in Tregs have been described in patients with T1D. Adoptively transferred autologous polyclonal expanded Tregs (exTregs) were safe and well-tolerated in prior phase 1 clinical trials. The Sanford/Caladrius Trex trial, a double-blinded, placebo-controlled, multi-center exploratory Phase 2 study, assessed a single treatment with exTregs (1-24x106cells/kg) in adolescents with recent-onset T1D (NCT02691247). Overall, exTreg therapy did not preserve the residual β-cell function, quantified as change over two years in C-peptide AUC-mean during a mixed meal test (p=0.39). However, the dose of exTregs and outcome varied greatly across subjects, providing a dataset that can be queried for correlates to outcome. Ex vivo fold expansion of exTregs (246 ± 149.9-fold, range 24.3-643-fold) negatively correlated with C-peptide change (r=-0.33, p=0.01), suggesting that infused Tregs may influence the outcome. Indeed, exTregs expressed more CD25, CD38, HLA-DR, and CXCR3 than endogenous Tregs. Preliminary analysis of a subset of subjects (n=32) shows a transient increase of total Tregs in treated subjects. Additionally, no significant changes in conventional T cell differentiation and activation after exTreg therapy compared to placebo were observed to date. By contrast, the dose of exTregs did not correlate with the preservation of beta cell function (r=-0.15, p=0.25), nor did peak frequency (day 7 post-infusion) of Tregs following treatment, suggesting that Treg number does not predict outcome. Instead, the activation state of exTregs may impact outcome. Studies are ongoing to characterize the endogenous and exTregs from treated (n=63) and placebo (n=44) subjects.
