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Response to Treg therapy is linked to rate of ex vivo Treg expansion

ABSTRACT: Background: CD4+CD25hiCD127lo/-FOXP3+ regulatory T cells (Tregs) play a key role in preventing autoimmunity. In type 1 diabetes, adoptive transfer of autologous polyclonal Tregs has been shown to be safe in adults in Phase I clinical trials. Methods: We explore factors contributing to efficacy in autologous polyclonal expanded Tregs (expTregs) Phase 2 clinical trial in 111 children and adolescents with new-onset type 1 diabetes (Sanford/Lisata Therapeutics Trex Phase 2 clinical trial) randomized 1:1:1 high and low treatment to placebo. Cytometry, bulk and single cell RNA-seq were perfomed on selected expTregs and PBMC samples from subjects. Results: A single dose of expTreg therapy (1-24x106cells/kg) was safe but did not prevent the decline in residual beta cell function over one year compared to placebo (p=0.39), regardless of age, baseline C-peptide, or dose of expTregs. ExpTregs were highly activated and suppressive, and a transient increase of activated memory Tregs was detectable one week after infusion in the high dose cohort, suggesting effective transfer of expTregs. However, in vitro fold expansion on expTregs varied across subjects even when accounting for age. Lower fold expansion and its’ associated gene signature was linked with better outcome, regardless of Treg dose. Conclusion: These results suggest that expTregs quantity alone does not alter outcome; instead, expTreg quality may be an important factor contributing to the efficacy of adoptive Treg therapy to prevent type 1 diabetes progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243270 | GEO | 2024/04/15

REPOSITORIES: GEO

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Project description:BACKGROUND: Preclinical studies have demonstrated that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a combination of plerixafor and low-dose tacrolimus (MRG-001) improves wound healing, promotes tissue regeneration and prevents allograft rejection. This first‐in‐human phase I dose‐escalation study evaluates the safety, tolerability, pharmacokinetics and pharmacodynamics of MRG-001, a novel fixed-dose combination drug. METHODS: In this Phase 1, double‐blind, randomized, placebo-controlled study, multiple ascending dose (MAD) cohorts are randomized to receive MRG-001 containing up to 0.02 mL/kg (plerixafor 24 mg/mL and tacrolimus 0.5 mg/mL) or saline placebo, subcutaneously every other day (SC, QAD) for 5 days (ClinicalTrials.gov: NCT04646603)The primary outcome is safety and tolerability. Safety and functional assessments are performed throughout the study. Blood samples are collected to evaluate systemic exposure. Fluorescence-activated cell sorting analysis and RNA expression of peripheral blood mononuclear cells (PBMCs) are used to evaluate the pharmacodynamics. RESULTS: Fourteen subjects received MRG-001 and 7 received a placebo. MRG-001 is safe and well-tolerated over the selected dose range. No deaths or severe adverse events are reported. There are no clinically significant laboratory changes after MRG-001 administration, apart from the predicted generalized leukocytosis. The intermediate dose group (0.01 mL/kg) showed the most significant white blood cell mobilization over time and increased by 2-4 fold from baseline and returned to baseline levels prior to the next injection. Circulating immune cells including FOXP3+ regulatory T cells and hematopoietic stem cells (CD45IntCD34+) increased significantly after MRG-001 injection. PBMC RNA sequencing and gene set enrichment analysis revealeds 31 down-regulated pathways in the intermediate dose MRG-001 group compared to no changes in the placebo group. CONCLUSION: MRG-001 is safe and well-tolerated across the full dose ranges tested. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration. A Phase II trial to treat severely and critically ill COVID-19 patients with MRG-001 has been initiated (NCT04646603) and a second phase II trial will explore the potential of MRG-001 to accelerate wound healing (NCT05844527),

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Response to Treg therapy is linked to rate of ex vivo Treg expansion

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