First-in-human phase i/ii clinical trial of ig-tregs for gvhd prevention

Background & Aim Our approach for GvHD prevention aims to mimic the paradigm of fetomaternal tolerance. HLA-G is an immunomodulatory molecule expressed in the placenta to protect the foetus from maternal rejection and is normally epigenetically silenced. In preclinical studies, we epigenetically modulated T cells in a clinical scale GMP protocol to produce a potent induced-Treg population enriched in HLA-G+ T-cells(iG-Tregs). We herein present the study protocol of the first-in-human phase I/II clinical trial of iG-Tregs and the monitoring assessment of the first patient(IG01) included(EUDRACT2021-006367-26). Methods, Results & Conclusion We conduct a phase I/II, dose escalation(0,1/0,5/1,5x106iG-Tregs cells/kg) study in adult patients undergoing allo-HCT from an HLA-matched sibling donor, which serves as the donor for iG-Tregs manufacturing. The primary objective is to assess the safety and the maximum tolerable dose of iG-Tregs and the secondary objective is to assess the efficacy in preventing GvHD. Patient and donor eligibility is evaluated at d+30 after allo-HCT, donor undergoes leukapheresis, and infusion is performed 4 weeks(W) later. aGVHD≥II at any time before infusion leads to exclusion. Product is released after standard QC testing and should contain≥10%HLA-G+CD3+cells. After infusion, the patient undergoes pharmacological immunosuppression tapering. Product and patient samples are also analysed for their phenotype(Cytek) and their TCR repertoire(Illumina).IG01 is a 58 y/o female with high-risk AML who underwent allo-HCT(CMV+/+) from her 51 y/o female sibling. The final iG-Tregs product contained 60x106cells, 82,3% CD3+ cells and 13,52% HLAG+CD3+ cells. iG-Tregs infusion(5,6x106 cells; 0,1x106/kg) took place on d+64 followed by cyclosporine tapering. The patient did not present infusion-related toxicities, remained GvHD-free, disease-free, without CMV reactivation with no other complications up to last follow-up(d+231). Integrated molecular and phenotypic monitoring of IG01 revealed an initial rise in HLA-G+ T-cells at W1 (baseline vs W1; 3,69% vs 4,88%), retention of 7,2% of iG-Tregs-derived TCR clonotypes at W4, and increase of CD4+CD25+CD127- nTregs at W8 post-infusion(baseline vs W8; 2,06% vs 3,56%)(Figure 1).This is the active first-in-human phase I/II study of iG-Tregs in the context of GvHD. IG01 displayed excellent clinical outcome with initial data hinting at the possible transient iG-Tregs persistence in vivo and intricate interplay within the T cell compartment.