Combined therapy with CD4⁺CD25highCD127⁻ T regulatory cells and anti‐CD20 antibody in recent‐onset type 1 diabetes is superior to monotherapy: Randomized phase I/II trial

Abstract

Aims: Monotherapy with autologous expanded CD4 + CD25 high CD127 À T regulatory cells (Tregs) or rituximab has been documented to slow disease progression in patients with recent-onset type 1 diabetes mellitus (T1DM). Whether a combined therapy including both drugs would further benefit this patient population is unknown. Materials and Methods:We conducted a three-arms clinical trial to explore the efficacy and safety of the combined treatment with Tregs and rituximab in paediatric patients with T1DM. The patients were allocated to three groups: Tregs only (n = 13), Tregs + rituximab (n = 12) and control (n = 11). The key primary efficacy analyses were C-peptide levels (mixed meal tolerance test) and the proportion of patients in remission at 12 and 24 months.Results: At month 24, as compared with the control, both treatment groups remained superior in the area under the curve of C-peptide mixed meal tolerance test, whereas in the analysis of all visits only the combined therapy improved area under the curve at 12 and 24 months. The proportion of patients in remission was significantly higher in the combined group than in the control group at 3, 6, 9 and 21 months but not at 18 and 24 months. There was no significant difference between the Tregs only group and control group. Adverse events occurred in 80% patients, mostly in the combined group and Tregs only group. No adverse events led to the withdrawal of the intervention or death. All comparisons were performed with alpha level of 5%. Maciej Zieli nski, Magdalena _ Zali nska contributed equally to this work.

An antigen-specific immunotherapeutic, AKS-107, deletes insulin-specific B cells and prevents murine autoimmune diabetes

“…Moreover, the antigen-specific function of AKS-107 may work synergistically in combination with the recently FDA-approved anti-CD3 mAb therapeutic, teplizumab, if administered during Stage 2 , for prevention or delay of Stage 3 T1D ( 50 , 51 ). Indeed, a recent clinical study in pediatric T1D subjects demonstrated positive outcomes upon treatment with T reg cell therapy followed by CD20 + B cell depletion therapy (i.e., rituximab) ( 23 ). AKS-107 is positioned for clinical safety and efficacy studies as a mono- or combination-therapy intended to prevent progression to overt diabetes.…”

Factors Governing B Cell Recognition of Autoantigen and Function in Type 1 Diabetes

“…Combined B and T cell-targeted therapy increased efficacy in a clinical trial investigating Treg and rituximab combination therapy, as compared to Treg therapy or insulin therapy alone [ 147 ]. A recent clinical trial showed that combination therapy with AG019, a bacteria genetically modified to express human proinsulin and human IL-10, and teplizumab led to stabilization or improvement in all measured metabolic variables up to 12 months and significantly increased exhausted CD8+ T cells at 6 months compared to AG019 monotherapy or placebo controls [ 148 ].…”

“…A recent clinical trial showed that combination therapy with AG019, a bacteria genetically modified to express human proinsulin and human IL-10, and teplizumab led to stabilization or improvement in all measured metabolic variables up to 12 months and significantly increased exhausted CD8+ T cells at 6 months compared to AG019 monotherapy or placebo controls [ 148 ]. It should be noted that rituximab alone or teplizumab alone controls were not included in these studies to confirm that the increased efficacy was not solely due to rituximab or teplizumab treatment, respectively [ 147 , 148 ].…”

Ofatumumab for the treatment of refractory anti‐LGI1 encephalitis with long‐term poor blood glucose control in type 1 diabetes

“…5 Rituximab, an anti-CD20 monoclonal antibody, has been used to treat type 1 diabetes and autoimmune encephalitis with proven efficacy. 6,7 After decades of pharmacological development, fully humanized anti-monoclonal antibodies have been produced.…”