Discussion
immune disorders
DISEASE PROGRESSION, TYPE 1 DIABETES, AUTOIMMUNE DISEASES, IMMUNE DISORDER, COMPLICATIONS
The prevalence of type 1 diabetes has surged in the last decade, partly due to non-genetic factors such as increased BMI and industrialisation [The use of MSCs in the treatment of immune disorders, including autoimmune diseases, has demonstrated their potential as a safe interventive therapy for type 1 diabetes. The aim of this study was to assess the safety and efficacy of the WJMSC drug product, ProTrans, in maintaining endogenous insulin production to slow the progression of type 1 diabetes.Previous clinical studies with MSCs have used various cell sources (e.g. bone marrow, fat or umbilical cord). MSCs from different sources have distinct properties and advantages based on production method, mode of administration, formulation and clinical indication for which they are employed [Principally, type 1 diabetes clinical trials have been conducted using autologous MSCs. In addition to known limitations of autologous drug products, Davies et al [The umbilical cord has the advantage of generating large quantities of cells from an easily accessible tissue, allowing generation of a commercially viable batch size of product, without the need to age the cells in vitro to levels that may jeopardise their functionality or safety [As ProTrans is an allogeneic cell therapy originating from multiple donors who are not HLA-matched; signs of HLA immunisation were investigated during dose escalation and only men were included. No HLA immunisation was seen on infusion of the product. With these safety data, women were included in part B of the study. Data from the efficacy study confirmed no HLA immunisation in the additional participants, indicating that the use of allogeneic cells did not influence safety with regard to histocompatibility antigen differences.Of the doses tested, 25, 100 and 200 million cells, all met the safety requirements. AEs were reported in all dose groups but were mild to moderate. No significant differences in AEs were reported between the doses evaluated and no SAEs related to treatment were recorded. Despite the inclusion of only three participants in each dose group, the highest dose (200 million cells) significantly preserved endogenous insulin production during the first year after treatment. These data provided the preliminary evidence for choice of dose in part B of the study. ProTrans, unlike other cell products reported, uses a fixed dose of cells rather than a particular number of cells per kg body weight. This is the first time a significant effect on maintenance of endogenous insulin production has been documented using a fixed number of MSCs. Fixed dosing offers distinct advantages for commercialisation of a cell therapy product, as the batch of cells produced directly relates to the number of individuals who can be treated, with no wastage of cells or the need for post-release processing to count cells or formulate them according to an individual’s weight. This means that ProTrans can be a true, ‘off-the-shelf’ product, thawed at bedside with no waiting period for the individual being treated.With the inclusion of ten participants within part B of the trial, it was necessary to use two batches of ProTrans product, derived from different umbilical cord donors. As part of the analysis in this study we compared participant response in terms of the primary endpoint using stratification based on the batch of product used. Both batches demonstrated no notable differences in safety or efficacy, suggesting low batch-to-batch variability of the product, a key feature for an allogeneic cell therapy.The primary efficacy endpoint was ∆-change in C-peptide AUC at 12 months post treatment. As seen with the preliminary results of the dose escalation study, a single administration of ProTrans induced significant retention of endogenous insulin production compared with placebo. This was also reflected clinically, with the participants receiving ProTrans requiring no change in exogenous insulin treatment at 12 months compared with their respective baseline requirements. This was in contrast to placebo-treated participants, who exhibited the expected increase in insulin requirements with disease progression. It should be noted that a significantly higher level of C-peptide was evident pre treatment in the ProTrans-treated group than in the placebo control group (The lack of difference in HbAThe data presented here support growing evidence that MSCs represent an attractive interventive therapy for slowing the progression of type 1 diabetes. An i.v. route was also employed in a previous study in which autologous bone marrow-derived MSCs were administered to adults newly diagnosed with type 1 diabetes [The long-term therapeutic effect of a single infusion of MSCs remains to be ascertained. Participants from this study will be monitored for an additional 4 years to investigate the safety and long-term efficacy of ProTrans treatment. Since the natural course of type 1 diabetes is to lose most endogenous insulin production during the first 5 years [We conclude that ProTrans, composed of WJMSCs, is safe in the tested dose range of 25–200 million cells when administered intravenously, and that a single treatment in adults recently diagnosed with type 1 diabetes with 200 million cells results in preservation of their endogenous insulin for at least a year. Long-term follow-up is ongoing to investigate treatment safety and efficacy persists and to determine whether repeated treatment with ProTrans will be necessary for maintaining endogenous insulin production, thereby slowing disease progression and reducing the risk of type 1 diabetes-associated complications.