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
CD19 CAR T cells have demonstrated promising efficacy in SLE by deeply depleting B cells, but these autologous cell therapies are expensive to deploy, come with significant toxicity risks, and lack the ability to control additional immune cell functions driving autoreactive B cell generation and lupus pathogenesis.
We developed GNTI-350, an allogeneic hypoimmune CD19 CAR—engineered regulatory T cell (CAR19 EngTreg) therapy, which leverages stable FOXP3 expression, a CD19 CAR for selective targeting, and a rapamycin-inducible IL-2 signaling complex to sustain Treg function.
Persistence of GNTI-350 is enabled by Immune Evasion Engineering (IEE), a hypoimmune technology that allows MHC-deficient allogeneic cell therapies to evade host NK cell clearance. Human CAR19 EngTregs expressed canonical Treg markers, suppressed T cell proliferation, blocked B cell differentiation into plasma cells, and depleted CD19+ B cells in humanized mice with minimal inflammatory cytokine release versus conventional CD19 CAR T cells. In the SLE123 mouse model, CAR19 mEngTregs persisted >4 months, lowered autoantibodies, improved kidney pathology, and reduced the levels of T follicular helper (Tfh) and germinal center (GC) B cells - potentially showing a reinforcement of T follicular regulatory (Tfr) cell function.
These data show that GNTI-350 can safely achieve a durable immune reset and may provide superior therapeutic benefit over CAR-T approaches to patients with B cell—driven autoimmune diseases.
Venture capital, NIH
Therapeutic Approaches to Autoimmunity (THER)
P. Zarin, Chris B. Moore, Travis Drow et al.· Journal of Immunology· 0 citations