A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes
Christine Bender, Alice Wiedeman, Alex Hu, Alyssa Ylescupidez, William K. Sietsema, Kevan C. Herold, Kurt Griffin, Stephen E. Gitelman, S. Alice Long, on behalf of the T-Rex Study Group†, Peter A. Gottlieb, R. Strock, Lexie Chesshir, María J. Redondo, Christopher T. Williams, Mark A. Clements, Wayne V. Moore, Linda A. DiMeglio, Megan Legge, M. Mullen, Juan Manuel Sepúlveda-Sánchez, Maria Spall, Stéphanie Woerner, Jason L. Gaglia, Brittany Resnick, Nora Bryant, Suzanne Krishfield, J J Turley, Nisha Koshy, Mikayla Mackey, Ines Guttmann‐Bauman, Rebecca Fitch, Lynn Bartholow, John Shelso, Alaa Al Nofal, K. Hanisch, Luis E. De Las Casas, Brenda Thurlow, Michael Gottschalk, Marla Hashiguchi, Lisa Paglia, Angela Y. Lam, Srinath Sanda, Christine Torok, Rebecca Wesch, Daniel J. Moore, William E. Russell, Tyler Jordan Smith, Anne Brown, Faith Brendle, Michael J. Haller, Miriam Cintrón, David A. Baidal, Della Matheson, Carlos Blaschke, Antoinette Moran, Elizabeth Pappensus, Janice Leschyshyn, Anne Street
Abstract
CD4 + CD25 hi CD127 lo/− FOXP3 + regulatory T cells (T regs ) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal T regs has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded T regs (expT regs ) 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 6 cells/kilogram) or low-dose (1 × 10 6 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expT regs and peripheral blood samples from participants. The single doses of expT regs were safe but did not prevent decline in residual β cell function over 1 year compared to placebo ( P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpT regs were highly activated and suppressive in vitro. A transient increase of activated memory T regs was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expT regs . However, the in vitro fold expansion of expT regs 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 reg dose. These results suggest that a single dose of polyclonal expT regs does not alter progression in T1D; instead, T reg quality may be an important factor.