A 360° review of immunotherapy for autoimmune diseases of type 1 diabetes are listed here:
Immunotherapy for autoimmune diseases of type 1 diabetes: Antigen-specific trials
Two mainly large trials: the DPT-1 trial, in which parental insulin was administered to individuals with positive autoantibodies, and the ENDIT trial in which individuals with positive autoantibodies were enrolled and received nicotinamide, failed to show any signifi-cant effect on halting the progression of the disease. The administration of oral insulin to first- and second-degree relatives of individuals with T1D at high genetic risk for developing T1D, showed some beneficial. Preservation of stimulated C-peptidewas then observed in T1D individuals treated with DiaPep277,an immunomodulatory peptide derived from heat-shock protein (hsp60), compared to a placebo group at 10 months post-treatment(C-peptide levels: 0.93 vs. 0.26 nmol/L).
Immunotherapy for autoimmune diseases of type 1 diabetes: Anti-inflammatory trials
Pozzili and colleagues performed a clinical study comparing the effect of vitamin E and nicotinamide (NA) combined with intensive insulin therapy in individuals with T1D. A slight increasein C-peptide values over 1 year after diagnosis (C-peptide levels:0.2 nmol/l) was reported in groups of treated subjects; how-ever, larger studies did not confirm this effect. orcalcitrol, when administered alone at a dose of 0.25 g to individ-uals diagnosed within 9 weeks with recent-onset T1D, alsodid not improve-cell function. Two other trials basedon the administration of Diazoxide, an ATP-sensitive K+channelactivator and inhibitor of insulin secretion, to pediatric diabeticsubjects combined with multiple daily insulin injections, showed a temporary increase in C-peptide concentration.
Immunotherapy for autoimmune diseases of type 1 diabetes: T/B cell trials
A small clinical trial based on the use of ATG in individuals with T1D along with intensified insulin therapy showed an improvement in cell function with lower exogenous insulin requirements and complete remission in 18% of subjects.However, data recently published from the large ATG trial, now published did not show any effects. Based on preclinical studies in diabetic NOD mice, many clinical trials were initiate dusing humanized monoclonal antibody against CD3 (e.g. anti-CD3, hOKT3 gamma1(Ala-Ala), Teplizumab) in individuals with T1D. The first two trials did not include a placebo group and reported preservation of endogenous C-peptide secretion with a decrease in exogenous insulin requirement, with 5% of individuals achieving insulin independence at 1 year. A phase 3 trial using teplizumab (14-day full-dose) showed that at 1 year after after treatment, 29% of treated individuals had HbA1c <7% and insulin dose requirements <0.5 U/kg per day. A randomized controlled trial with 2 courses of treatment with Teplizumab administered 2 weeks after diagnosis to individuals with new onset T1D, showed an overall preservation of -cell mass revealed by a reduction in the decline of C-peptide levels at 2 years compared to placebo group. In a post hoc analysis, a group of clinical responders was characterized to reveal insights on potential issues involved in the failure of this regimen, including lower frequency of Th-1 cells andof IFN- producing CD8+. In another study, authors showed an improvement in cell function and higher C-peptide levels insubjects treated with Rituximab compared to placebo, along with lower HbA1c levels and lesser insulin requirement. Finally,Abatacept (CTLA-4–Ig) administered for 2 years has demonstrated mild effects on C-peptide levels. T/B cell-targeting trials appear efficacious enough to induce some metabolic effects, but not powerful enough to establish insulin independence.
Immunotherapy for autoimmune diseases of type 1 diabetes: Cytokine trials
Etanercept, a recombinant soluble TNF- receptor fusion protein that binds to TNF-α, to pediatric individuals newly diagnosed with T1D. After 24 weeks of Etanercept treatment, a significant decrease in HbA1c was observed compared to the placebo group. Conversely, a very disappointing result was obtained when using Rapamycin together with IL-2. All individuals treated with Rapamycin and IL-2 showed a decrease in C-peptide values over the course of 3 months with an increase in insulin requirement. Two trials based on IL-1 antagonists (Canakinumab[a human monoclonal anti-interleukin-1] and Anakinra [a humaninterleukin-1 receptor antagonist]) failed to show any statistically significant differences compared to placebo groups. Targetingone cytokine likely will not cure T1D, due to the redundancy of pro-inflammatory cytokines involved in the onset and maintenance of the disease.
After a thorough review of all clinical trials used to treat T1D, AHSCT remains the only therapy that has achieved a satisfactory rate of remission in T1D individuals. It is likely that this combinational approach serves to reset the immune system of individuals with T1D. However, the occurrence of diffuse adverse effects requires improvement of this approach before it can be used to treat a larger number of individuals with T1D.
Nasr M B et al. The rise, fall, and resurgence of immunotherapy in type 1 diabetes[J]. Pharmacological Research, 2015, 98: 31-38.