the interest in these types of intervention [42, 43]. The drug, a modified form of anti‐CD3 antibody that minimizes first‐dose side effects, was studied by comparing 12 subjects aged 7 to 30 who were treated with the antibody to an equal number of patients in a control group who did not receive the drug. One year after treatment with anti‐CD3, the treated patients produced more insulin and needed less insulin therapy than the untreated patients. Those who received the antibody treatment also had better HbA1c levels. The anti‐CD3 was designed to act on the immune system's T‐cells in a more specific manner than previous attempts at immune intervention in early diabetes.
Most recently, a phase 2, randomized, placebo‐controlled, double‐blind trial showed that a single 14‐day course of teplizumab (an Fc receptor–nonbinding anti‐CD3 monoclonal antibody) significantly slowed progression to clinical T1D in high‐risk, nondiabetic relatives of patients with diabetes who had at least two autoantibodies. At the conclusion of the trial, the percentage of diabetes‐free persons in the teplizumab group (57%) was double that in the placebo group (28%). Median delay in the diagnosis of diabetes was 2 years. However, the cohort was relatively small, and the estimated power limited. Furthermore, authors did not assess the potential development of antibodies to teplizumab, which would be a concern [44].
In the DEFEND‐1 and DEFEND‐2 phase III trials, anti‐CD3 antibody Otelixizumab revealed a narrow therapeutic window. At a low dose, there was no preservation of β‐mass [45]. This was indeed observed at 18 months, but with significant adverse effects. Otelixizumab is a chimeric monoclonal antibody that targets the CD3/T‐cell receptor, which is genetically modified by removing the glycosylation site in the Fc domain, thus affecting binding of complement or Fc receptors. This reduces secondary reactions due to cytokine release. Otelixizumab downregulates pathogenic T‐cells and upregulates T‐reg cells, thus halting the autoimmune process in T1D.
Only one trial has focused on β‐cell function in T1D after treatment with Rituximab, which produces B cell depletion [46]. Although T1D is a T‐cell mediated autoimmune disorder, B lymphocytes play a pathogenetic role by acting as antigen‐presenting cells (APC) and modulating the islet environment. In recent‐onset T1D subjects, administration of Rituximab reduced HbA1c levels and exogenous insulin demand due to the preservation of C‐peptide levels over 1 year. Interestingly, after 2 years' follow‐up, Rituximab delayed the decrease in C‐peptide levels but did not influence insulin dose, suggesting B cell deletion is not sufficient to restore β‐cell tolerance.
FIG 2.3 T1D clinical research over the past 10 year. Atkinson MA, Roep BO, Posgai A et al. The challenge of modulating β‐cell autoimmunity in type 1 diabetes. Lancet Diabetes Endocrinol 2019;7(1):52–64.
TABLE 2.2 Current TrialNet studies. (Source: www.trialnet.net)
| Study | Status | Description |
|---|---|---|
| Teplizumab Prevention Study | Completed | This study tested the drug teplizumab to see if it could delay or prevent progression of early stage T1D (stage 2) and prevent clinical diagnosis (stage 3). |
| Oral Insulin Prevention Study | Completed | This study tested the drug oral insulin to see if it can delay or prevent T1D (stage 1) from progressing to stage 2 and ultimately prevent clinical diagnosis (stage 3). |
| Hydroxychloroquine (HCQ) | Currently Enrolling | This study tests the drug hydroxychloroquine (HCQ) to see if it can delay or prevent early stage T1D (stage 1) from progressing to abnormal glucose tolerance (stage 2) and ultimately prevent clinical diagnosis (stage 3). |
| ATG/GCSF New Onset Study | Completed | This study was designed to build on prior findings of a pilot study suggesting thymoglobulin (ATG) combined with pegylated granulocyte colony stimulating factor (GCSF) preserved insulin production for more than 1 year after treatment in people who had type 1 diabetes for 4 months to 2 years. |
| Abatacept Prevention Study | Currently Not Enrolling | This study tests the drug abatacept to see if it can delay or prevent progression of early stage T1D (stage 1 or stage 2), and ultimately prevent clinical diagnosis (stage 3). |
| Pathway to Prevention | Currently Enrolling | This study screens and observes relatives of people with type 1 diabetes to learn more about how the disease occurs |
The use of immunosuppressive drugs has also been proposed as a possible approach to decelerate the evolution of the disease.
In a multicenter, double‐masked, randomized controlled trial, Abatacept (CTLA4‐Ig) has been administered on days 1, 14, 28, and then every 28 days through a 30 min intravenous infusion at a dose of 10 mg/kg [47]. Results from this study showed that Abatacept was more efficient compared to placebo in preserving the β‐cell mass, as evidenced by stimulated C‐peptide secretion. However, the effect diminished with time; therefore, further investigation will be necessary in order to unravel whether the beneficial effect persists after cessation of infusions. Indeed, Abatacept is a potential candidate to be used in tertiary prevention trials, and is a candidate for use in combination therapies for recent‐onset T1D patients.
GAD65 (the 65 kDa isoform of glutamic acid decarboxylase) is a human enzyme that has an important role in the nervous system and in several nervous system diseases, e.g. Parkinson's disease and chronic pain.
GAD65 is also found in the insulin producing β‐cells of the pancreas, although its function at this site is not yet fully established. It is however clear that GAD65 is one of the most important targets when the immune system attacks the insulin producing β‐cells in autoimmune diabetes. Thus, treatment with rhGAD65 is thought to induce tolerance to GAD65, thereby intervening in the autoimmune attack and preserving the capacity to produce insulin in patients with autoimmune diabetes.
Although ongoing studies are investigating whether rhGAD65 can preserve β‐cell function in recently diagnosed individuals with T1D, trials carried out to date do not demonstrate a significant reduction in the loss of stimulated C‐peptide in recently diagnosed children and young adults (10–20 years) with T1D over a 15‐month period [48].
GAD65 was also targeted in NOD mice in order to reduce the number of GAD65‐specific T effector cells [49], achieving normoglycemia in 70% of NOD mice. Based on this findings, antigen‐based immunotherapy therapy with subcutaneous GAD‐alum have been tested to slow down the course of loss of insulin in patients with recently diagnosed T1D. Recently, the prevention trial DIAPREV‐IT has showed that GAD‐Alum as a subcutaneous prime and boost injection was safe in prediabetic young children but did not affect progression to T1D [50]. The beneficial for prevention of T1D of GAD‐alum should be tested in future prevention studies.
TABLE 2.3 Immunotherapy trials that are awaiting, or currently recruiting, participants. (Source: www.clinicaltrials.gov)
| ClinicalTrials.gov identifier |
|
|---|
