Journal of Endocrinological Investigation

, Volume 40, Issue 8, pp 803–814 | Cite as

Immunotherapy for type 1 diabetes

  • Davide Frumento
  • Moufida Ben Nasr
  • Basset El Essawy
  • Francesca D’Addio
  • Gian Vincenzo Zuccotti
  • Paolo Fiorina
Review

Abstract

Introduction

Although many approaches have been tested to overcome the insulin dependence caused by the pancreatic β-cells destruction observed in individuals affected by type 1 diabetes (T1D), medical research has largely failed to halt the onset or to reverse T1D.

Methods

In this work, the state of the art of immunotherapy will be examined, and the most important achievement in the field will be critically discussed. Particularly, we will focus on the clinical aspect, thus avoiding the tedious preclinical work done in NOD mice, which has been so poorly translated to the bedside.

Conclusions

Stem cell therapies achieved thus this far the most promising results, while immune ablation and standard immunosuppressants did not maintain the premises of preclinical results. The next step will be to generate a feasible and safe clinical approach in order to cure the thousands of patients affected by T1D.

Keywords

Type 1 diabetes Immunotherapy Trials Clinical 

Introduction

Type 1 Diabetes (T1D) is characterized by an autoimmune reaction, which is thought to be led by autoreactive T cells, in which the pancreatic β-cells are aggressively and selectively destroyed, causing the body not to produce any insulin, so that the glycemic control is impaired [1]. T1D is influenced by several factors, including genetic polymorphisms, vitamin deficiencies, as well as bone marrow, and circulating stem cells defects [2, 3, 4, 5]. Elevated glucose levels lead to many complications, such as accelerated atherosclerosis, retinopathy, nephropathy, neuropathy, ketoacidosis, osteopenia, and infections [6, 7]. Intensive insulin administration is known to be very effective in controlling hyperglycemic episodes and in reducing diabetic complications. However, diabetic complications are not fully abrogated by insulin therapy [8, 9], while the increasing incidence of hypoglycemia still limits a too aggressive insulin approach, although technological advances have clearly improved blood glucose management, while still exposing patients to chronic peripheral over-insulinization [1, 10, 11]. Indeed, the above-mentioned technological innovations made difficult to compare the cost-to-benefit ratio of immunotherapy versus emerging insulin treatment systems [12]. Pancreas and islet transplantation, although interesting experimental procedures were developed, are limited by few number of donors by chronic immunosuppression and by the recurrence of autoimmunity/onset of alloimmunity [1]. Additionally, pancreas transplant has been only partially successful [13], likewise has been a recent quercetin-based method to differentiate bone marrow mesenchymal stem cells into β-cells, which has not yet been translated to animal models [14]. In this review, we will revisit the state of the art of clinical work and studies related to the use of immunotherapy to prevent or revert T1D.

Cell-depleting strategies

Given the supposed, and only partially demonstrated in human, pancreatic T/B cells in T1D, approaches aiming at the depletion of T or B cells were tested. In 1979, a monoclonal antibody (OKT3) directed to a CD3 complex subunit, i.e., ε chain, was developed [15]. OKT3 monoclonal antibodies (mAb) were tested and used to prevent allograft rejection in kidney transplantation [15, 16]. The effect of anti-CD3 monoclonal antibodies was the tested in T1D. Twelve patients, aged between 7.5 and 30, received a 14-day course of antibody administered intravenously (1.42 μg/kg of body weight on day 1, 5.67 μg/kg on day 2, 11.3 μg/kg on day 3, 22.6 μg/kg on day 4, and 45.4 μg/kg on days 5 through 14). The treatment seemed to halt the insulin production decay for at least 1 year [17]. In another anti-CD3-based trial called DEFEND-1, carried out on 80 new-onset patients (aged from 12 to 39), six daily infusions of 8 mg of anti-CD3 mAb were able to reduce C-peptide loss by about 25% [18]. Interestingly, in another study, anti-CD3 mAb (Teplizumab) preserved C-peptide response up to 60 months after been administered to a cohort of 10 patients aged from 7 to 30 for 12 days [19]. A 2-year-study, carried out in the context of the Protégé trial, which enrolled a cohort of 763 patients cohort (aged from 8 to 35), Teplizumab prevented the β-cells mass decline and preserved C-peptide levels [20]. Teplizumab was also proven to reduce the lowering of C-peptide levels in T1D patients (2 years from onset) in another randomized open-label trial named AbATE Study (a Protégé prosecution), in which 52 patients aged between 8 and 30 where treated with a 14-day course at increasing concentrations (from 51 to 826 μg/m2) [21]. A Phase 3 trial called DEFEND-2 was supposed to be the ultimate confirmatory proof on the striking effects of anti-CD3 mAb; indeed, the trial was unsuccessful. An 8-day Otelixizumab (anti-CD3 mAb) treatment was administered to 179 patients aged from 12 to 17 through intravenous infusions. Unfortunately, C-peptide levels were not different from the baseline [22]. A follow-up of AbATe Study is currently being carried out in order to measure C-Peptide following a mixed meal tolerance test (MMTT) in 44 patients with an age between 10 and 37 years (NCT02067923). NIDDK is now recruiting 170 individuals aged between 8 and 45 to test if anti-CD3 mAb could delay or prevent T1D onset in high-risk relatives. The trial is a randomized and double-blind one, and intravenous infusions of anti-CD3 monoclonal antibody will be administered for 14 days (NCT01030861). Different anti-CD3 mAb-based trials are still in the recruiting phase; like one which plan to recruit 40 patients aged from 16 to 27 to be treated with an intravenous 6-days course of anti-CD3 mAb (Otelixizumab) at increasing concentrations (from 9 to 36 mg diluted in 0.9% physiological solution), in order to halting/slowing β-cell destruction (NCT02000817).

After the attempts with anti-CD3 mAb, investigators started to explore the possible use of Antithymocyte Globulin (ATG), a rabbit-derived antibody commonly used to treat and prevent organ transplant rejection [23]. A group of 58 individuals aged between 12 and 35 was recruited and treated with 6.5 mg/kg of ATG (i.e., Thymoglobulin®), while placebo was administered as a saline solution. No statistical difference was observed in the ATG-treated as compared to the placebo group [24]. A possible explanation of the failure was the presence of homeostatic proliferation in autoreactive T cells, possibly resistant to the depletion. Thus, investigators tried to take advantage of the synergism between ATG and CSF (to fill the space created by ATG with more immature and less autoreactive clones) and carried out a randomized single-blind study on 25 patients who received intravenous ATG (2.5 mg/kg) and subcutaneous pegylated G-CSF (6 mg every 2 weeks for 6 doses). C-peptide loss was reduced, and its levels in the treated group after a MMTT were statistical different as compared to placebo (delta = 0.31 nmol/l) [25]. A double-blind Phase 2 study sponsored by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, United States) experimented the use of associated with granulocyte CSF (G-CSF). A cohort of 84 patients aged between 12 and 45 was enrolled and subjects received 2.5 mg/kg of ATG with two divided intravenous infusions within 16 h, while G-CSF was given subcutaneously every 2 weeks, for a total of 6 doses. Outcomes are under analysis and results have still not been released (NCT02215200).

Based on a couple of very relevant preclinical studies from Yale and Harvard, Investigators started B cell-depleting studies as well. In the first preclinical study, carried out by our group at Harvard, CD22 receptor on B cells was targeted with an anti-CD22 monoclonal antibody to deplete B cells in NOD mice [26]. The experiment gave a prolonged B cells depletion and delayed disease in pre-diabetic mice and reverted hyperglycemia; indeed, the same results were obtained by the Yale group of Li Wen [26, 27]. Interestingly, Pescovitz et al. [28] run a clinical trial with Rituximab (anti-CD20 mAb) in order to deplete B cells. A total of 126 patients affected by T1D and aged from 8 to 45 were recruited to undergo a double-blind Phase 2 study, in which four intravenous infusions of Rituximab (375 mg/m2 of body surface) were given within 22 days. Rituximab preserved β-cells reserve, while it had no effect on reverting T1D [28].

T cell-depleting strategies with anti-CD3 and ATG were among the most promising based on preclinical studies; indeed, the clinical results were quite disappointing. While a slowing in the decline of β-cells function was observed in most of the trials, the reversal of the disease was quite rare if absent. It is possible that monotherapy with depleting agents is not the correct answer for T1D and that a combinational approach is required. We should mention that most of the trial with T/B cells depleting strategies were associated with adverse effects (e.g., cytokine release, fever infections) and thus may not be tested in the prevention of T1D but with reversal only (Table 1).

Table 1

List of cell-depleting clinical trials

Cell-depleting trials (authors)

Description

Outcomes

C-peptide (AUC—nmol/l/min)

Herold et al. (2002) [17]

Anti-CD3 mAb in newly diagnosed T1D

C-peptide loss reduced

Treated: 1.28–1.27

Control: 1.48 to 0.74

Keymeulen et al. (2005) [18]

Insulin needs after anti-CD3 mAb in newly diagnosed T1D

C-peptide loss reduced

Treated: 0.85 to 0.80

Control: 0.95–0.70

* Data were extrapolated from graphics

Herold et al. (2009) [19]

Single course of anti-CD3 mAb (Teplizumab) in newly diagnosed T1D

C-peptide loss reduced

Treated: 0.88 ± 0.18–0.89 ± 0.25

Control: 0.41 ± 0.12–0.19 ± 0.12

Pescovitz et al. (2009) [28]

Rituximab, B-Lymphocyte Depletion, and Preservation of Beta-Cell Function

C-peptide loss reduced

Treated: 0.75 ± 0.39–0.56 ± 0.06

Control: 0.74 ± 0.37–0.47 ± 0.08

Sherry et al. (2011) [20]

Teplizumab (anti-CD3 mAb) in newly diagnosed T1D (Protégé study): 1-year results from a randomized, placebo-controlled trial

C-peptide loss reduced

Treated (variation): −0.06

Control (variation): −0.14

* Data were extrapolated from graphics

Herold et al. (2013) [21]

Teplizumab (Anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders

C-peptide loss reduced

Treated: from 0.72 ± 0.08–0.44 ± 0.12

Control: from 0.67 ± 0.12–0.21 ± 0.09

Ambery et al. (2014) [22]

Efficacy and safety of low-dose Otelixizumab anti-CD3 mAb in preserving C-peptide secretion in newly diagnosed T1D adolescent: DEFEND-2, a randomized, placebo-controlled, double-blind, multicenter study

Ineffective

Values were not significantly different

Haller et al. (2015) [25]

Antithymocyte globulin (ATG) plus G-CSF treatment preserves β cell function in newly diagnosed T1D

C-peptide loss reduced

Treated: 0.71 ± 0.48–0.74 ± 0.47

Control: 0.71 ± 0.44–0.43 ± 0.32

Gitelman et al. (2016) [24]

Antithymocyte globulin ATG in newly diagnosed T1D: a 2 year randomized trial

Ineffective

Values were not significantly different

National Institute of Diabetes and Digestive and Kidney Diseases—Bethesda, MD, United States (2016) [NCT02215200]

Antithymocyte Globulin (ATG) and Pegylated Granulocyte Colony-Stimulating Factor (G-CSF) in newly diagnosed T1D

Results have still not been released

National Institute of Diabetes and Digestive and Kidney Diseases—Bethesda, MD, United States (2016) [NCT01030861]

Anti-CD3 mAb (Teplizumab) for prevention of diabetes in relatives at risk for T1D

Ongoing

GlaxoSmithKline—Verona, Italy (2016) [NCT02000817]

A single-blind, randomized, placebo-controlled, repeat dose, dose escalating study investigating tolerability pharmacokinetics, pharmacodynamics and the beta-cell preserving effect of Otelixizumab in newly diagnosed T1D

Ongoing

Yale University—New Haven, CT, United States (NCT02067923) [2016]

Autoimmunity-blocking Antibody for Tolerance in Recently Diagnosed T1D (AbATE) Follow-Up Study

Ongoing

mAb (monoclonal antibody); T1D (type 1 diabetes); AUC (Area Under the Curve)

Antigen-specific strategies

Because of the safety and the possible less striking effect, antigen-specific strategies were generally tested in prevention studies. Probably the most important antigen-based trial was the double-blind Phase 3 Diabetes Prevention Trial of Type-1 (DPT-1) carried out in order to evaluate if insulin could prevent diabetes onset in high-risk relatives. A total of 71,148 individuals (aged from 3 to 45) were enrolled and screened for cytoplasmic islet cell antibodies (ICAs). Positive subjects were divided in two groups, i.e., parenteral and oral insulin administration groups. Results evidenced that both strategies were ineffective in preventing T1D onset [29]. However, because some effect was observed in the subgroup with high-insulin autoantibody (IAA) treated with oral insulin, some follow-up clinical trials have been employed [30]. NIDDK is carrying out a Phase 3 double-blind study in which oral insulin was given to a cohort of 400 T1D patients aged between 3 and 45, aiming to induce a protective immunity and consequently halt the autoimmune ongoing attack. Therapy was given as 7.5 mg capsules before breakfast on a daily basis (NCT00419562). Moreover, the same institution is performing a Phase 2 open-label efficacy study in which 40 participants (between ages 3–45) will be administered orally with 67.5 mg/day insulin crystals for 6 months and with 500 mg/day insulin crystals given every other week for the following 6 months (NCT02580877). Another double-blind Phase 2 trial sponsored by Technical University of Munich (Germany) tested the administering of oral insulin in multiple islet autoantibody-positive children (NCT02620072).

Recently, because glutamic acid decarboxylase (GAD) has been supposed to be involved in T1D onset, a double-blind Phase 2 clinical trial funded by NIH was performed aiming to assess if GAD-based immunization could maintain insulin production in recent onset T1D patients. A cohort of 126 people aged between 3 and 45 was treated with GAD-Aluminum Hydroxide (GAD-alum). GAD-alum injections did not affect nor ameliorate the course of insulin secretion decay during 1 year in treated individuals [31]. Interestingly, Linkoeping University is carrying out an interventional Phase 1 open-label study, in which 15 patients (age 12–30) will be administered with three 4 µg lymph node injections of GAD-Alum (Dyamid®), one per month, in order to evaluate how this compound can influence immune system and endogenous insulin secretion (NCT02352974). Treatment will be administered during 12 months adopting the following dose escalation schedule: 7.5 mg/day or placebo for 3 months, increasing to 67.5 mg/day or placebo for the following 9 months (follow-up will continue for 24 months). The study is currently recruiting participants, and the estimated cohort will count 220 individuals. Finally, the King’s College (United Kingdom) is enrolling 24 patients aged from 18 to 45 to be treated with a novel drug named MultiPepT1De (mixture of peptides from islet auto antigens). A row of 6 injections will be administered within 20 week at low, medium, and high doses (NCT02620332).

Antigen-specific therapies have been considered the “Holy Grail” of immunotherapy for many years. Unfortunately, it seems that they may have an effect, if any, in the early phase of T1D onset, or in pre-diabetes, while they appeared ineffective later on. However, the lack of adverse effects makes this area of investigation super attractive (Table 2).

Table 2

List of antigen-specific clinical trials

Antigen-specific trials (authors)

Description

Outcomes

C-peptide (AUC—nmol/l/min)

Diabetes prevention trial—Type 1 diabetes study group (2002) [30]

Effects of insulin in relatives of patients with T1D

Ineffective

Some protection in high IAA group

Values were not significantly different

Wherret et al. (2011) [31]

Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent onset type 1 diabetes: a randomized double-blind trial

Ineffective

Values were not significantly different

King’s College London (2015) [NCT02620332]

Multiple islet peptide administration in T1D (MultiPepT1De)

Ongoing

National Institute of Diabetes and Digestive and Kidney Diseases—Bethesda, MD, United States (2016) [NCT02580877]

Exploring immunologic effects of oral insulin in relatives at risk for T1D

Ongoing

Technical University of Munich—München, Germany (2016) [NCT02620072]

Mechanistic study using oral insulin for immune efficacy in secondary prevention of T1D

Ongoing

National Institute of Diabetes and Digestive and Kidney Diseases—Bethesda, MD, United States (2016) [NCT00419562]

Oral Insulin for prevention of diabetes in relatives at risk for T1D

Ongoing

Linköping University - Linköping, Sweden (2017) [NCT02352974]

Open-Label Pilot Trial in Adults with Recent onset T1D to Evaluate the Safety, Diabetes Status and Immune Response of GAD-antigen (Diamyd®) Therapy Administered into Lymph Nodes in Combination with an Oral Vitamin D Regimen

Ongoing

AUC area under the curve; T1D type 1 diabetes; GAD glutamic acid decarboxylase

Anti-inflammatory strategies

Since inflammation was recognized as a condition predisposing β-cells destruction, many trials based on anti-inflammatory molecules were carried out. Crinò et al. [32] performed a randomized trial experimenting on a cohort of 64 patients with recent T1D onset (both sexes, mean age 8.8 years) giving Nicotinamide alone (25 mg/kg body weight) and in combination with Vitamin E (15 mg/kg), with the objective of improving metabolic control and the residual β-cells functionality. As a result, both treatments, along with an intensive insulin administration, were able to preserve basal C-peptide secretion up to 2 years after diagnosis [32]. Moreover, Gottlieb et al. tested Mycophenolate mofetil alone (600 mg/m2 body surface, given in 2/3 doses within 2 years) and associated with Daclizumab (1 mg/kg body weight through intravenous infusions at day 0 and 2 weeks later) in a randomized double-blind Phase 2 study in which 126 patients were enrolled (aged from 8 to 45, both genders) to evaluate if these strategies could stop the β-cells destruction. Both treatments had no effect [33]. According to Sobel et al. [34], Cyclosporin A (7.5 mg/kg/day for 6 weeks and then 4 mg/kg/day for 12 months) associated with Methothrexate (5 mg/kg/w for 12 months) was able to induce the remission of T1D. This paramount result was obtained in a non-randomized study that recruited 10 patients (aged from 8 to 18); indeed, after the treatment, insulin requirement was less than 0.25 units/kg/day and the HbA1c was less than 7.5%. Two anti-interleukin-1β (a pro-inflammatory cytokine) were employed in T1D. In the first one, a total of 69 individuals (age 6–45) were treated for 12 months with a 2.0 mg/kg monthly injection of Canakimumab (a fully human anti-interleukin-1β monoclonal antibody) [35], while in the second one, a group of 69 patients, aged from 18 to 35, was administered for 12 months with daily 100 mg injection of Anakinra (Interleukin-1 receptor antagonist) [36]. The meaningless difference in C-peptide AUC (Area Under the Curve) after a MMTT was 0.01 nmol/L between Canakinumab and placebo at 12 months, and 0.02 nmol/L between Anakinra and placebo [35, 36]. Anakinra was tested in a small Phase 2 efficacy study sponsored by Radboud University (Netherlands). Sixteens individuals (aged from 18 to 65) were administered via subcutaneous injection with 100 mg of Anakinra for 1 week on a daily basis. While glycemic control improved, as evidenced by the decrease in mean glucose levels from 9.71 ± 0.45–8.33 ± 0.40 mmol/l, the relative small number of patients included did not allow a solid conclusion [37]. An anti-TNFα monoclonal antibody-based formulation (Golimumab, SIMPONI®) is about to be tested in a randomized, double-blind Phase 2 study, in which 81 patients (aged from 6 to 21, both genders) will be administered with subcutaneous injections intermittently for 52 weeks (NCT02846545). The legacy of immune intervention in T1D possibly started with anti-inflammatory drugs; unfortunately, this was associated with a plethora of adverse effects. However, it is likely some sort of anti-inflammatory strategies may be needed to achieve the full remission of T1D (Table 3).

Table 3

List of anti-inflammatory clinical trials

Anti-inflammatory trials (authors)

Description

Outcomes

C-peptide (AUC—nmol/l/min)

Crinò et al. (2004) [32]

A randomized trial of nicotinamide and vitamin E in children with recent onset T1D (IMDIAB IX)

C-peptide loss reduced

*NA: 0.32 ± 0.20–0.43 ± 0.20

*NA + vitamin E: 0.32 ± 0.20 0.25 ± 0.20

*Patients diagnosed over 9 years of age, 9 months after treatment

Gottlieb et al. (2010) [33]

Failure to Preserve β-Cell Function With Mycophenolate Mofetil and Daclizumab Combined Therapy in Patients With New- Onset Type 1 Diabetes

Ineffective

Values were not significantly different

Sobel et al. (2010) [34]

Cyclosporine and methotrexate therapy induces remission in type 1 diabetes mellitus

Remission of the disease

Problems related to drug toxicity

Parameter not measured

Moran et al. (2013) [35]

Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicenter, randomized, double-blind, placebo-controlled trials

Ineffective

Values were not significantly different

Van Asseldonk et al. (2015) [37]

One week treatment with the IL-1 receptor antagonist Anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus

Insulin sensitivity improved for 4 weeks (determined by euglycemic hyperinsulinemic clamp)

Below the detection limit

Janssen Research & Development, LLC— Titusville, NJ, United States (2016) [NCT02846545]

SIMPONI® to Arrest β-cell Loss in Type 1 Diabetes

Still in recruiting phase

AUC area under the curve; T1D type 1 diabetes; IL-1 interleukin-1

Cell therapy strategies

Different cell types have been considered in T1D for their “regulatory” properties: from T cells to dendritic cells and lately to B cells [38, 39, 40, 41]. A double-blind Phase 1 study, in which a total of 10 T1D patients (aged from 18 to 60) were recruited and treated with 10 million autologous dendritic cells [42], gave mixed results. Cells were administered every 2 weeks via abdominal intradermal injections and were well tolerated, with no relevant adverse reactions, and induced an increase in peripheral B220+ CD11c B cells population, but no real effect on glycemia [43]. Furthermore, a Phase 2 study (randomized, double blind) based on a similar principle was recently designed by DiaVacs Inc. Twenty-four participants aged from 12 to 35 will be treated with leukapheresis-derived dendritic cells (incubated with antisense DNA oligonucleotides) (NCT02354911).

Bluestone et al. developed a novel technique to isolate and expand regulatory T cells (TRegs) from T1D patients. The expanded TRegs maintained their T cell receptor diversity and exhibited functional activity [44] and were tested in an open-label Phase 1 trial in T1D patients. A total of 14 adult individuals, in four dosing cohorts (0.05 × 108–26 × 108 cells), received ex vivo–expanded autologous CD4+CD127lo/CD25+ polyclonal TRegs. Almost 25% of cells were detectable into the bloodstream after 1 year, and the results encourage the feasibility of a phase 2 trial [44]. An ongoing open-label trial is being performed to test Treg+Interleukin 2 (IL-2) in 16 patients (age 18–45) with recent onset T1D, who will receive single infusions of autologous Tregs (with doses of 50 × 106, 350 × 106 or 1 × 109 cells respectively) and 1 × 106 IU/day of subcutaneous IL-2 for 5 days (NCT02772679). The same cell type will be used in an open-label study aimed to evaluate the efficacy of administering ex vivo expanded umbilical cord blood Tregs to T1D patients. A total of 40 individuals, aged from 6 to 60, will be treated with a single infusion of Tregs given in a 1–5 × 10/kg of body weight dose (NCT02932826). A Phase 2 randomized double-blind trial is about to be performed on 111 patients (aged from 12 to 17) in order to verify the effect of autologous ex vivo expanded polyclonal Tregs. This will be done by administering a single infusion of CLBS03, a formulation containing autologous Tregs, in a low (group 1) or high dose (group 2) (NCT02691247). Finally, in another trial, the powerful immunoregulatory effect of Tregs will be combined with the known positive β-cells effects of GLP1R agonist. Forty T1D patients (minimum age 18) will receive a single infusion of umbilical cord blood Tregs in a dose of 2 × 106 cells in total and Liraglutide (an incretin-mimetic molecule) in a dose escalation of up to 1.2 mg that will be started 3 days after the Tregs infusion and will be given at that dose daily for 6 months (NCT03011021). Regulatory T cells hold great promises and the work of Bluestone group is moving in the direction of having a product to be used for T1D individuals (Table 4).

Table 4

List of cell therapy clinical trials

Cell therapy trials (authors)

Description

Outcomes

C-peptide (AUC-nmol/l/min)

Giannouakis et al. (2011) [43]

Phase I (Safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients

Frequency upregulation of a potentially beneficial B220+ CD11c B cell population

Treated: ND to 1.10

Control: ND to < 0.50

* Data were extrapolated from graphics

Bluestone et al. (2015) [44]

Type 1 diabetes immunotherapy using polyclonal regulatory T cells

Good survival of the T regulatory cells, with up to 25% remaining into the bloodstream after 1 year

Values were not significantly different

DiaVacs, Inc.—La Jolla, CA, United States (2015) [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

This study is not yet open for participant recruitment

University of California—Berkeley, CA, United States (2016) [NCT02772679]

A Phase 1 trial of CD4 + CD127lo/-CD25 + Polyclonal Treg adoptive immunotherapy with interleukin-2 for the treatment of type 1 diabetes

Ongoing

Second Xiangya Hospital of Central South University—Changsha, China (2016) [NCT02932826]

Phase 1/ phase 2 study of the therapeutic effect of Ex vivo expanded umbilical cord blood regulatory T cells on autoimmune diabetes

Ongoing

Caladrius Biosciences, Inc.—New York, NY, United States (2016) [NCT02691247]

A prospective randomized placebo-controlled double-blind clinical trial to evaluate the safety and efficacy of CLBS03 (autologous Ex vivo expanded polyclonal regulatory T cells) in adolescents with recent onset type 1 diabetes mellitus (T1DM)

Ongoing

Second Xiangya Hospital of Central South University—Changsha, China (2017) [NCT03011021]

Phase 1/ phase 2 study of the therapeutic effect of Ex vivo expanded umbilical cord blood regulatory T cells With liraglutide on Autoimmune diabetes

Ongoing

AUC area under the curve. TReg regulatory T cells

Stem cells strategies

The field of T1D immunotherapy has been shaken up by the appearance of some strong results associated with the use of hematopoietic stem cells [45]. However, words of caution should be used to avoid unnecessary enthusiasm.

An open-label Phase 1/2 study sponsored by the Uppsala University Hospital, in which 20 patients (aged between 18 and 40) were transplanted with autologous MSCs at a dose of approximately 2 × 106 cells/kg body weight. The immunomodulatory properties of MSCs were demonstrated by different papers by our group in the NOD models [46, 47, 48, 49, 50]; indeed, MSC-treated patients exhibited a reduced decay in C-peptide levels after treatment [50]. Umbilical cord blood MSCs (UC-MSCs) were tested in association with autologous bone marrow mononuclear cell (aBM-MNC) in a randomized open-label trial, in which 42 individuals (age 18–65) were infused through the pancreatic artery with 1.1 × 106/kg UC-MSC and 106.8 × 106/kg aBM-MNC. At 1 year after treatment, insulin requirements decreased by 30% and AUC C-Pep increased [51]. Many other trials, some of which are clearly disputable, are now trying to test the use of MSCs from different sources in T1D, including the use of allogenic adipose-derived MSCs. Two intravenous doses of allogenic adipose-derived MSCs and 106 cells/kg body weight of autologous bone marrow mononuclear cells (BMC) will be given (NCT02940418). An open-label phase 2/3 trial sponsored by the General Committee of Teaching Hospitals and Institutes (Egypt) enrolled participants (total number will be 20, aged between 18 and 60) aiming to test an intravenous first infusion of purified exosomes ranging from 40 to 180 nm, plus a second one consisting in MSC-microvescicles ranging from 180 to 1000 nm (NCT02138331).

A breakthrough was published in 2007 in JAMA, when authors described a Phase 1/2 trial on 15 patients of both genders aged from 14 to 31. Patients with newly diagnosed T1D received immunosuppression and autologous Hematopoietic Stem Cells (HSCs). Cells were infused after cyclophosphamide conditioning (200 mg/kg) and rabbit antithymocyte globulin (4.5 mg/kg). After the treatment, all patients but 1 became insulin independent for at least 6 months, with increased C-peptide levels and decreased anti-GAD auto antibodies [52]. Recently, the worldwide results of the use of autologous nonmyeloablative HSC transplantation in 65 individuals aged from 12 to 35 (both genders) were published [53]. A combination of cyclophosphamide, ATG and granulocyte colony-stimulating factor (G-CSF) were given, followed by the infusion of cryopreserved CD34+ as a single infusion. Among the treated patients, 59% reached insulin-independence and 32% remained insulin independent at the last follow-up (48 months) [53].

Although this approach is still limited by adverse events related to the strong immunosuppression, the use of immunoregulatory stem cells is a very hot path to be pursued in order to find a cure for T1D (Table 5).

Table 5

List of stem cell clinical trials

Stem cells trials (authors)

Description

Outcomes

C-peptide (AUC-nmol/l/min)

Voltarelli et al. (2007) [52]

Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus

14 out of 15 patients became insulin independent for at least 6 months

0.40 ± 0.31–1.34 ± 1.15

Qingdao University—Tsingtao, China (2010) [NCT01219465]

Safety and efficacy of umbilical cord mesenchymal stem cells infusion for initial Type 1 diabetes

Ongoing

General Committee of Teaching Hospitals and Institutes – Cairo, Egypt (2014) [NCT02138331]

Phase 1 study of the effect of cell-free cord blood derived microvescicle on β-cell mass in type 1 diabetes mellitus (T1DM) patients

Ongoing

D’Addio et al. (2014) [53]

Autologous nonmyeloablative hematopoietic stem cell transplantation in new-onset type 1 diabetes: a multicenter analysis

32% of patients remained insulin independent at the last follow-up checkpoint and all treated subjects exhibited an HbA1c concentration decrease, as well as a C-peptide concentration increase

0.54 ± 0.06–1.22 ± 0.10

Carlsson et al. (2015) [50]

Preserved β-cell function in type 1 diabetes by mesenchymal stromal cells

Slight C-peptide loss reduced

Treated: 0.29 ± 0.05–0.32 ± 0.05

Control: 0.28 ± 0.02–0.29 ± 0.04

Cai et al. (2016) [51]

Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: A pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion

Improvement in insulin requirement and C-peptide levels

Treated: 0.04 ± 0.03–0.08 ± 0.05

Control: 0.05 ± 0.04–0.04 ± 0.03

University of Jordan—Amman, Jordan (2016) [NCT02940418]

The use of mesenchymal stromal cells (MSC) in type 1 diabetes mellitus in adult humans: phase I clinical trial

Not yet opened for participants

AUC area under the curve

Conclusions

In conclusion, although many unsuccessful attempts were done in order to prevent or revert T1D, we are moving in the right direction to find a feasible and safe cure for those thousands of people affected by T1D that are demanding an alternative to daily insulin injections.

Notes

Compliance with ethical standards

Conflict of interest

We have no potential conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study formal consent in not required.

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Copyright information

© Italian Society of Endocrinology (SIE) 2017

Authors and Affiliations

  • Davide Frumento
    • 1
  • Moufida Ben Nasr
    • 2
    • 3
  • Basset El Essawy
    • 4
  • Francesca D’Addio
    • 1
    • 2
  • Gian Vincenzo Zuccotti
    • 5
  • Paolo Fiorina
    • 2
    • 3
  1. 1.DITIDSan Raffaele HospitalMilanItaly
  2. 2.International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo e Enrica Invernizzi, Department of Biomedical and Clinical Science L. SaccoUniversity of MilanMilanItaly
  3. 3.Nephrology Division, Boston Children’s HospitalHarvard Medical SchoolBostonUSA
  4. 4.MedicineAl-Azhar UniversityCairoEgypt
  5. 5.Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. SaccoUniversity of MilanMilanItaly

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