Allogeneic cell therapies offer a scalable and off-the-shelf alternative to the autologous approach, but immune rejection, particularly by natural killer (NK) cells following human leukocyte antigen (HLA) ablation, remains a major barrier to their persistence. Here, we report an improved synthetic NKG2A engager to selectively inhibit NKG2A⁺ NK cells while avoiding activation of NKG2C⁺ subsets, thereby overcoming a key limitation of the natural ligand HLA-E. Engineered regulatory T cells (EngTregs) lacking HLA and expressing the engager were protected from in vitro NK cell-mediated cytotoxicity more effectively than previously reported NK inhibitory strategies. In humanized mouse models, EngTregs persisted for up to 12 weeks, whereas unprotected cells were rapidly rejected. Incorporation of the engager into a clinically compatible dual-AAV EngTregs preserved Treg identity and function while conferring resistance to immune rejection. Together, these findings establish the improved NKG2A engager as an effective synthetic immune-evasion strategy and provide a clinically translatable approach to enable durable persistence of off-the-shelf EngTreg therapies.
Tingxi Guo, Kaya Epstein, M. Hoover et al.· EMBO Molecular Medicine· 0 citations
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.
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.
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.
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.
Bristol Myers Squibb provided initial funding.
Therapeutic Approaches to Autoimmunity (THER)
Martina Sassone-Corsi, J. Yam, Abigail Doherty et al.· Journal of Immunology· 0 citations
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