A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes.

CD4CD25CD127FOXP3 regulatory T cells (T) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal T has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded T (expT) in a randomized phase 2 multi-center, double-blind, clinical trial (Sanford/Lisata Therapeutics T-Rex phase 2 trial, ClinicalTrials.gov NCT02691247). One hundred ten treated children and adolescents with new-onset T1D were randomized 1:1:1 to high-dose (20 × 10 cells/kilogram) or low-dose (1 × 10 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expT and peripheral blood samples from participants. The single doses of expT were safe but did not prevent decline in residual β cell function over 1 year compared to placebo ( = 0.94 low dose, = 0.21 high dose), regardless of age or baseline C-peptide. ExpT were highly activated and suppressive in vitro. A transient increase of activated memory T was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expT. However, the in vitro fold expansion of expT varied across participants, even when accounting for age, and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of T dose. These results suggest that a single dose of polyclonal expT does not alter progression in T1D; instead, T quality may be an important factor.