Engineering allogeneic type 1 regulatory T cells: a scalable, off-the-shelf platform for restoring immune tolerance.

Type 1 regulatory T (Tr1) cells are IL-10-producing CD4+ regulatory T cells that play a central role in maintaining peripheral immune tolerance. Prior investigations of autologous Tr1 cell-based therapies have demonstrated clinical promise in graft-versus-host disease (GvHD), but widespread clinical application has been constrained by challenges in scaling cell production. TRX103 is an engineered, allogeneic Tr1 cell therapy manufactured using a fully compliant, current Good Manufacturing Practice-compatible process. TRX103 is generated by pooling engineered CD4+ T cells from three healthy donors that have been transduced with a lentiviral vector encoding human IL-10 and a truncated human nerve growth factor receptor, CD271. In vitro, off-the-shelf TRX103 suppressed effector T cell proliferation and inhibited pro-inflammatory cytokine production by monocytes from both healthy donors and patients with Crohn's disease. In vivo, TRX103 homed to intestinal tissues and prevented disease development in a xenogeneic GvHD model. Phenotypic and functional analyses of TRX103 revealed the acquisition of a distinct cellular identity characterized by reduced expression of activation and immune synapse-associated molecules and minimal allogeneic stimulatory capacity. Together, these findings define a distinct immunomodulatory profile for TRX103 and support its clinical development as a scalable allogeneic cell therapy for immune-mediated diseases. TRX103 is currently being evaluated in a Phase 1/2a study in treatment-refractory Crohn's disease (NCT06721962) and a Phase I study for GvHD prevention in hematopoietic stem cell transplantation recipients (NCT06462365).