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Other strategies for prevention of β‐cells damage with immune intervention at onset of the disease are based on immunotolerance (monoclonal antibodies, antigen‐based treatments, pro‐inflammatory cytokine‐based treatments) (Figure 2.3, Tables 2.2 and 2.3).

In the last decades, experience obtained with the use of the antiCD3 monoclonal antibody in two studies (one in the USA and the other in Europe) has revitalized 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	Title	Intervention	Primary outcome
NCT02307695	The Effect of Saxagliptin on Glucose Fluctuation and Immune Regulation in Patients with Type 1 Diabetes	Saxagliptin	MAGE at 24 weeks
NCT01559025	Evaluation of Vildagliptin (Galvus®) as add‐on to Insulin in Residual β‐cell Function and Inflammatory Markers in New‐onset Type 1 Diabetes Mellitus	Vildagliptin	MMTT C‐peptide at 3, 6, 9 and 12 month
NCT02442544	Effect of Prebiotic Fibre on Gut Microbiota, Intestinal Permeability and Glycaemic Control in Children with Type 1 Diabetes: A Pilot Randomized, Double Blind, Placebo Controlled Study	Prebiotic 1:1 oligofructose:inulin	HbA1C at 3 months
NCT02820558	A Phase I Study of Safety and Pharmacological Activity of Substance P in the Reversal of Recent‐Onset Type 1 Diabetes	Substance P	Safety at 20–27 days
NCT02505893	A Monocentric, Open‐label Pilot Study to Assess the Safety and Efficacy of Minimal Islet Transplantation in Patients with New‐onset Type 1 Diabetes	ATG + pG‐CSF + rapamycin + human pancreatic islet	Safety and MMTT C‐peptide at 12 months
NCT02940418	Use of Stem Cells in Diabetes Mellitus Type 1	AD‐MSCs + BM‐MNCs	Safety at 6 months
NCT02293837	EXTEND	Tocilizumab	MMTT C‐peptide at 12 months
NCT02617654	A Randomized, Double‐blinded Placebo‐controlled, Paralleled Designed, Investigator Sponsored Study of the Effect of the GLP‐1 Receptor Agonist Liraglutide on Β‐cell Function in C‐peptide Positive Type 1 Diabetic Patients	Liraglutide	MMTT C‐peptide at 12 months
NCT03170544	A Single Ascending Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of MK‐1092 in Healthy Subjects and in Subjects With Type 1 Diabetes Mellitus	MK‐1092	Safety and maximal glucose infusion rate at 33 days
NCT02814838	A Phase 2, Multicentre, Randomized, Double‐blind, Placebo‐controlled Study in Patients with New‐onset Type 1 Diabetes	Ladarixin	MMTT C‐peptide at 13±1 weeks
NCT02411253	DIABIL‐2	rhIL‐2	MMTT C‐peptide at 12 months
NCT02803892	MONORAPA	Rapamycin /+ Vildagliptin	MMTT C‐peptide at 4±1, 12±2 weeks
NCT02218619	Clinical Investigation of Efficacy of Tauroursodeoxycholic Acid (TUDCA) to Enhance Pancreatic Β‐cell Survival in Type 1 Diabetes by Reducing Endoplasmic Reticulum Stress	Tauroursodeoxycholic Acid (TUDCA)	MMTT C‐peptide at 6, 12, and 18 months
NCT03272269	A Phase I Placebo‐controlled, Double‐blind, Dose Escalation Clinical Trial to Evaluate the Safety and Immune Responses of Imcyse's IMCY‐0098 in Patients With Recent Onset Type 1 Diabetes	IMCY‐0098	Safety at 24 weeks
NCT03032354	Effect of Lactobacillus Rhamnosus GG and Bifidobacterium Lactis BB 12 on Beta‐cell Function in Children With Newly Diagnosed Type 1 Diabetes ‐ a Randomized Controlled Trial	Probiotics	MMTT C‐peptide at 6 and 12 months
NCT02644759	Transplantation of Autologous Stem Cells for the Treatment of Type 1 Diabetes Mellitus	aLD‐SCs/CB‐MSCs + G‐CSF	Insulin requirement at 1 month
NCT02354911	A Randomized, Double‐Blind, Placebo‐Controlled, Cross‐Over Study of the Safety and Efficacy of Autologous Immunoregulatory Dendritic Cells in Patients With Type 1 Diabetes	Immunoregulatory Dendritic Cells	MMTT C‐peptide at 12 and 24 months
NCT02624804	A Pilot Study of the Therapeutic Potential of Stem Cell Educator Therapy in Type 1 Diabetes	Stem Cell Educator Therapy	Safety at 12 months
NCT02846545	T1GER	Golimumab	MMTT C‐peptide at 12 months
NCT03011021	Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes	UCB ‐ Tregs + Liraglutide	Safety at 24 months
NCT02932826	Safety Study and Therapeutic Effects of Umbilical Cord Blood Treg Cells on Autoimmune Diabetes	UCB ‐ Tregs	Safety at 24 months
NCT02384889	Targeting Polyamines Using DFMO in Persons with Type 1 Diabetes: A Randomized, Double‐Masked, Placebo‐Controlled Phase I Study to Evaluate the Safety, Tolerability, and Initial Pharmacodynamics of Multiple Ascending Doses	Difluoromethylornithine	Safety with dose escalation at 6 months
NCT03046927	Vitamin D and Residual Beta‐Cell Function in Type 1 Diabetes	Ergocalciferol	MMTT C‐peptide at 12 months
NCT01773707	CTLA4‐Ig (Abatacept)for Prevention of Abnormal Glucose Tolerance and Diabetes in Relatives At ‐Risk for Type 1	Abatacept	Abnormal glucose tolerance
NCT03298542	A Phase 1b Study to Evaluate SIMPONI (Golimumab) Therapy in Children, Adolescents and Young Adults With Pre‐Symptomatic Type 1 Diabetes	Golimumab	Safety at 26, 52, and 78 weeks
NCT03182426	Autologous Hematopoietic Stem Cell Mobilization (Plerixafor) and Immunologic Reset in New Onset Type 1 Diabetes Mellitus	Alemtuzumab + anakinra + etanercept + liraglutide + plerixafor	Safety and MMTT C‐peptide at 3, 6, 9, 12, 18, and 24 months
NCT02772679	TILT	Tregs + IL‐2	Safety and Treg proportion at 3 years
NCT02804165	Gene‐virus Interactions Implicated in Type 1 Diabetes	Enterovirus vaccination	T1D diagnosis
NCT03243058	A Randomized, Double Blind, Phase I/II Trial of Low‐Dose Interlekin‐2 Immunotherapy in Established Type 1 Diabetes	Proleukin (IL‐2)	MMTT C‐peptide at 12 months
NCT02081326	Repeat BCG Vaccinations for the Treatment of Established Type 1 Diabetes	BCG	HbA1C at 1,2,3,4 and 5 years
EudraCT: 2014‐004319‐35	TregVac2.0	Tregs + anti‐CD20 antibody	(Phase II Trial assessing expanded polytTregs in patients with recent onset Type 1 diabetes mellitus)
EudraCT 2014‐004760‐37	Incretin‐based therapy in non‐symptomatic, early diagnosed Type 1 Diabetics	Liraglutide	MMTT C‐peptide at 3, 6, 9, and 12 months

Pro‐inflammatory cytokine‐based treatments have proven to be safe and effective for treatment of various autoimmune diseases. Thus, inhibition of expression of those molecules can induce important changes in pancreatic β‐cells induce important changes in pancreatic β‐cells [51].

The aim of using the Anti‐Interleukin‐1 in newly diagnosed T1D subjects is to test the feasibility, safety/tolerability and potential efficacy of anti‐IL‐1 therapy in maintaining or enhancing β‐cell function in people with new onset T1D. Anti‐IL‐1 administration for rheumatoid arthritis has been proven to be well tolerated in patients [52, 53]. IL‐1 is also involved in T1D progression by activating T‐helper cells and improving the number of circulating memory T‐cells [54]. The active substance is interleukin‐1 receptor antagonist, a blocker of an immune‐signal molecule named interleukin‐1. Two randomized placebo‐controlled trials aimed to assess whether canakinumab, a human monoclonal anti‐interleukin‐1 antibody, or anakinra, a human interleukin‐1 receptor antagonist, improved β‐cell function in recent‐onset T1D, but their effectiveness was not demonstrated [54, 55].

More recently, the ongoing clinical trial EXTEND (Clinical trial NCT02293837; www.clinicaltrials.gov) is currently examining whether the blockade of IL‐6 signaling through tocilizumab, an anti‐IL‐6 receptor antibody, can induce a protection of β‐cell function in T1D patients (ages 6 to 17 years) (Table 2.3).

Interleukin‐8 appears to be another important mediator in the progression of T1D. Circulating levels of IL‐8 are elevated in children with T1D compared to non‐diabetic controls. Furthermore, levels of IL‐8 correlate with glycemic control, higher level being associated to poorer glucose control. As a result, the modulation or inhibition of IL8 activity may be a valid target for the development of novel treatments aimed to control the progression of T1D.

A multicenter, randomized, double‐blind, placebo‐controlled phase 2 trial of CXCR1/2 IL‐8 inhibitor (Ladarixin) has just presented its results at the American Diabetes Association's (ADA) 80th Scientific Sessions (Clinical trial NCT02814838; www.clinicaltrials.gov). The trial involved 76 patients with new‐onset T1D, randomly (2:1) assigned to receive either Ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off – treatment group) or placebo (control group). Although results indicated no statistically significant differences in stimulated C‐peptide at weeks 13 and 26, investigators noted 76.6% of patients receiving Ladarixin had an HbA1c below 7% and a daily insulin requirement of less than 0.50 IU/kg compared to just 45.8% of patients receiving placebo. Furthermore, in a prespecified subgroup analysis of patients with fasting C‐peptide below the median value of the trial population at baseline, MMTT AUC of C‐peptide trended at week 13 and reached statistical significance at week 26.