SUN-556 GNTI-122: A Potentially Curative Engineered Treg Cell Therapy for the Treatment of Recently Diagnosed Type 1 Diabetes

Abstract Disclosure: M. Gose: None. P. Sharma: None. A. Meiners: None. K. Hawkins: None. S. Albertson: None. S. Hussel: None. S. Yang: None. L. Webb: None. P. Saikumar-Lakshmi: None. G. Uenishi: None. M. Repic: None. J. Buckner: None. C. Patel: None. T. Chen: None. B. Christin: None. GNTI-122 is an autologous engineered regulatory T (EngTreg) cell therapy developed to treat recently diagnosed type 1 diabetes (T1D). The EngTregs are designed to overcome Treg instability, lack of TCR specificity, and IL-2 scarcity to halt progression of T1D. Patients diagnosed with T1D within 100 days will undergo apheresis, from which bulk CD4+ T cells will be purified. These cells will then be genetically modified to produce GNTI-122 by editing two loci to incorporate GentiBio's three core pillars that overcome challenges of traditional Treg cell therapies: (i) stabilized FOXP3 to preserve potent suppressive activity, (ii) IL-2 signaling support through a chemically induced signaling complex (CISC), activated by low-dose rapamycin, to promote engraftment and suppressive activity in an IL-2 deficient microenvironment, and (iii) a TCR targeting an islet-specific antigen (IGRP) to ensure homing to its target and suppress pathogenic T cells through direct and bystander suppression. GentiBio has developed plans for GNTI-122 clinical-scale production and characterization using healthy donor material, demonstrated proof-of-concept for research grade GNTI-122 using T1D patient donor material, and prepared a phase 1 trial to treat recently diagnosed T1D. The clinical-scale development process for GNTI-122 has been established using starting material from healthy donors, consistently generating highly functional EngTregs with over 90% purity of dual-edited product and cell yields exceeding 3X10^9 with high viability. The final product exhibits typical Treg markers such as FOXP3, CD25, low CD127, CTLA4, EOS, TNFRII, CD27, and low CD70. When stimulated, the cells show increased expression of LAP and GARP, markers indicative of an immune-suppressive profile, and decreased levels of pro-inflammatory cytokines (IL-2, TNF-α, and IFNγ). GNTI-122 demonstrates pSTAT5 signaling in response to IL-2 or rapamycin via the engineered CISC. Furthermore, GNTI-122 effectively suppresses T conventional cells (Tconv). Research grade GNTI-122 has also been generated from T1D patient donor material with similar phenotype and function as the clinical-scale GNTI-122. Importantly, GNTI-122 derived from T1D patient donors effectively suppressed the proliferation and pro-inflammatory cytokine secretion of autologous polyclonal pathogenic T cells targeting islet antigens, confirming the mechanism of action. GentiBio has planned a phase 1 trial to evaluate this innovative cell therapy in recently diagnosed adult T1D patients, scheduled to begin in the second half of 2025. Presentation: Sunday, July 13, 2025