Abstract Introduction Autologous polyclonal regulatory T cell (Treg) therapies hold promise for treating autoimmune and inflammatory bowel disease (IBD), but face challenges with specificity, stability, cost, long manufacturing times, inconsistent quality, and logistical complexity. Allogeneic approaches can overcome some of these barriers but introduce risks of immune rejection and graft-versus-host disease. Methods To address this, we developed GNTI-932, a precision-engineered, allogeneic, gut-targeted Treg therapy. GNTI-932 integrates four innovations: gut-specific targeting via synthetic binding receptors; stable Treg phenotype by FOXP3 overexpression in bulk CD4+ T cells; a rapamycin-inducible IL-2 signaling complex (CISC) supporting in vivo stability and purity; and immune evasive engineering (IEE) combining HLA class I/II knockout with a proprietary NK cell inhibitor to prevent rejection. Results In vitro, GNTI-932 showed a characteristic Treg phenotype (CD25, CTLA-4, LAP, GARP), suppressed effector CD4+ T cells, secreted no proinflammatory cytokines, and resisted allo-rejection. In vivo, murine surrogates localized to inflamed gut, minimized off-target trafficking, improved survival, reduced inflammation and restored mucosal integrity. GNTI-932 also persisted beyond 80 days, enabled by IEE. Conclusion GNTI-932 is a novel, hypoimmune, antigen-specific, off-the-shelf immunotherapy for restoring tolerance in IBD, designed to be scalable and affordable for widespread use. Funding Source Bristol Myers Squibb provided initial funding. Topic Categories Therapeutic Approaches to Autoimmunity (THER)
Sassone‐Corsi et al. (Tue,) studied this question.