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Home / Resources / Clinical Gems / ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt # 11: Interdiction, Part 3 of 3

ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt # 11: Interdiction, Part 3 of 3

Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor

ADA-JDRF-Type-1-Diabetes-Sourcebook-image

Prevention of β-cell Destruction and Preservation for Those with Existing Type 1 Diabetes

Jane Lee Chiang, MD, and Stephen E. Gitelman, MD

Role of Regulatory T-cells

In moving these studies from bedside back to bench, investigators have attempted to define what has been altered in the immune system that accounts for the success to date in these efforts. From immunological mechanistic assays of clinical samples, and from further evaluation in animal models with these agents, a leading thought now is that these therapies are not only functioning as depleting agents or in some direct way blunting T effector cells responses but in some cases may in turn foster the development of a novel population of T-cells, regulatory T-cells (Tregs), that serve to keep autoreactive T-cells in check. Tregs constitute a small percentage of CD4+ T-cells and are identified by their constitutive expression of CD25 (the α chain of the IL-2 receptor) and the transcription factor FoxP3. One critical factor in Treg development is the cytokine IL-2, and thus one could consider exogenous IL-2 to directly augment this cell population. The complexity that has emerged however is that the dose of IL-2 is critical in how the immune system is affected, with higher-dose IL-2 serving as a nonspecific activator of multiple immune cell subsets, including T-cells and Natural Killer (NK) cells, while low-dose IL-2 selectively augments Tregs.45….

IL-2 and rapamycin. One initial attempt to directly target this pathway has been an ITN-sponsored phase I trial with IL-2 (proleukin) plus rapamycin (sirolimus) (NCT00525889).46 The latter drug was added as a means to keep autoreactive T-cells in check while Tregs expanded. Tregs did indeed expand, but NK cells and eosinophils did as well. Investigators terminated the trial early when they noted a transient decline in β-cell function. It may have been related to the dosing and timing of rapamycin or IL-2, or both, but the exact cause is unclear. β-cell function subsequently stabilized, and of interest from the mechanistic studies was a persistent change in IL-2 signaling in Tregs at 12 months. It may be that such an approach will be feasible with optimal dosing of rapamycin and a lower dose of IL-2. Studies with lower-dose IL-2 alone have proven effective in graft vs. host disease and hepatitis-C–related vasculitis.47,48 A phase I/II, placebo-controlled trial is being conducted with low-dose IL-2 in T1D, investigating the relationship between low-dose IL-2 and Treg induction, and effects on β-cell function (Klatzmann, NCT01353833). Investigators are also considering alternate means to more selectively amplify Tregs via this axis. For example, there may be mutated forms of IL-2 that selectively bind to the receptor on target Tregs but not on other cell types, and thus do not confer the same risk for expansion of other cell types.

Therapeutic approaches with Tregs. As a means to bypass all the potential issues noted above, one could consider direct therapy with Tregs. Proof of principle has once again come from studies in the NOD mouse, where purified and ex vivo expanded Tregs given to mice with recent-onset T1D reverses the disease. Bluestone and colleagues subsequently developed a procedure for purifying and expanding a polyclonal Treg population for clinical use, and are conducting a phase I dose-escalation trial with autologous expanded Tregs (NCT01210664).49 Safety and possible efficacy in a phase I study of children with new-onset T1D based on this same expansion protocol has been reported.50 An open-label phase I trial in T1D subjects using umbilical cord blood (UCB), potentially another source of Tregs, has been conducted.51 The study showed that autologous UCB infusion was safe and did induce changes in Treg frequency, but the therapy failed to preserve C-peptide (NCT00305344).5 Follow-up studies using UCB coupled with vitamin D and omega-3 fatty acids are ongoing (NCT00873925). As with the drug trials, the challenge for these studies is to determine a safe and effective dose of cells. Rather than using polyclonal Tregs, investigators ultimately hope to develop more targeted clinical therapy with antigen-specific Tregs.

Additional Therapeutic Considerations

Other cellular therapies. Aside from augmenting Tregs, one can consider changing APCs. Toward this end, Giannoukakis et al. modified autologous monocyte-derived dendritic cells, treating the cells ex vivo with antisense phosphorothioate–modified oligonucleotides targeting costimulatory molecules.52 They hypothesize that these modified APCs will have immunosuppressive properties via impaired T-cell costimulation. In a phase I T1D trial, they have shown that treatment with these modified autologous dendritic cells is safe and well tolerated and may upregulate the frequency of potentially beneficial β-cells (NCT00445913).52 A larger phase II study is needed to further assess this approach.

An alternate approach to modifying T-cell activation has been noted in a phase I study in multiple sclerosis. Investigators are utilizing antigen coupled to peripheral blood leukocytes via ethylene carbodimide as a modified APC in an attempt to induce tolerance.53 Such an approach may also be adapted as a T1D therapy. It is notable that a variety of different antigens can be coupled to a single cell, as peptides of interest are further defined in T1D. This approach may be one means to present antigens for tolerance induction. Mesenchymal stem cell infusions are also being evaluated in new-onset T1D, with the goal that they may differentiate into β-cells in vivo, modulate the immune response, or both (NCT00690066).

Augmentation of β-cell mass. The approaches mentioned to date address means to abrogate autoimmune destruction of β-cells. However, therapies to enhance β-cell repair, regeneration, or neogenesis may also be an important synergistic approach. Animal models suggest that glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-IV) inhibitors have salutary effects. An ongoing new-onset T1D clinical trial with sitagliptin (DPP-IV inhibitor) and lansoprozole (GLP-1R agonist) (NCT01155284) will test this hypothesis. Other studies with related agents are also being considered for prevention and new-onset trials. Growth factors that have been evaluated in animal models and considered for clinical trials include insulin-like growth factor-1 (IGF-1) and islet neogenesis–associated peptide. Ultimately, one may consider β-cell replacement in those with new-onset T1D, particularly as more robust cells become available from stem cell–based approaches (see chapter 4). If the means become available to develop such cells from the affected individual, one would presume that immunotherapy would still be needed in the face of an ongoing autoimmune response, and thus the new-onset trials mentioned above will become quite important in informing the best choice of therapy to preserve such cells. Encapsulation could obviate the need for such immunotherapy, although there is ongoing concern about the integrity and function of such devices to date.

Rituximab. Despite the dogma that T1D is a T-cell–mediated disease, evidence from animal models suggests that β-cells, but not autoantibodies themselves, are involved in β-cell destruction. The hypothesis is that β-cells act as APCs, communicating with T-cells, and altering their behavior. To further explore this in a clinical trial, investigators conducted a phase II trial with an anti-CD20 mAb (rituximab) (NCT00279305).54 They found that a single course of therapy resulted in a statistically significant difference in β-cell function at 1 year in the treatment vs. the placebo group. C-peptide was preserved in the treated group for 8.2 months, but thereafter the rate of decline in C-peptide was parallel between the drug-treatment and placebo groups. Adverse events included infusion reactions, depletion of β-cells (as expected) with low recovery over 1 year, and persisting lower IgM levels. These findings provide novel insights into the complexities of the autoimmune process in T1D, and highlight the potential role of other cell types in this process. Future studies could include repeated dosing with this or related anti-β-cell therapies in new-onset T1D, as has been used in other autoimmune disorders such as rheumatoid arthritis, although concern lies in risk from infectious diseases following chronic β-cell depletion. This approach is also under consideration for T1D prevention.

Metabolic control. Outside of the realm of immunology, one approach to preserve β-cell function is intensive glycemic control. In the DCCT, it was noted that improved metabolic control seemed to preserve β-cell function.55,56 Another study, of an intensive 2-week inpatient treatment shortly after diagnosis, with continuous intravenous insulin regulated by a Biostator, resulted in better β-cell function at 1 year, compared to conventional controls.57 One common observation from the aforementioned successful new-onset trials is a transient stabilization in β-cell function, for a variable period of time, followed by an inexorable decline in β-cell function that seems to parallel the control group, prompting speculation that there may be interplay between metabolic control, inflammation, and immune responses. TrialNet and DirecNet are collaborating to critically evaluate this concept: a randomized trial is evaluating subjects who receive intensive metabolic control, first with an in-hospital 5-day program utilizing a hybrid closed loop consisting of a continuous glucose sensor coupled with an insulin pump to optimize metabolic control. The algorithm uses every-minute glucose sensor readings to determine minute-by-minute pump insulin doses based on the present glucose, glucose rate of change, and pending insulin action. The subjects are followed at an outpatient program with open-loop sensor and pump. Subjects are compared to those in the control group, who pursue usual diabetes care through their regular provider (NCT00891995).

PRESERVATION TRIALS: FUTURE CONSIDERATIONS

Next Steps for β-cell Preservation Studies

The trials conducted to date have laid important groundwork for the next generation of studies. Each of these past studies had compelling preclinical or related clinical rationale, yet there is ongoing concern about what most consider lukewarm results to date. No single agent or trial has safely and effectively restored β-cell function for an extended period of time without the need for exogenous insulin therapy in the vast majority of participants. Based on these findings, where should the field go from here?

The last few decades have taught us that the immunological defects of T1D are complex and not completely understood: elucidation of the underlying pathophysiology may guide more rational trials. Insights will continue to be gained from T1D animal models such as the NOD mouse, but, at best, these models will have limitations; an inbred mouse strain with a T1D-like disease process only crudely approximates the complexities of the human clinical condition. Identifying other T1D animal models, aside from the NOD, may prove helpful. Humanizing the mouse immune system, in which the mouse immune system is essentially replaced with human components, may help recapitulate the human derangements of the immune system in a mouse model.

There may be no substitute for trying to gain further information directly from humans. Ideally, one would utilize clinical samples. However, very real limitations are posed by the inability to gain direct access to the pancreas and pancreatic lymph nodes, and instead relying on peripheral blood samples, where the autoreactive T-cell repertoire may be present at very low numbers. T-cell assays, such as the tetramer assay, make it possible to detect autoreactive T-cells present at very low frequency. Means to visualize β-cell mass and function in vivo are currently in development and will be a major advancement for clinical trials. Finally, much may be learned from the Network for Pancreatic Organ Donation (nPOD), an organized network collecting and archiving pancreata and other tissues from recently deceased individuals with T1D for further study.58

Next Generation Study Design

Most trials in new-onset T1D patients have been conducted with a single agent, and often with a placebo control group. In addition to the drugs currently available, the number of potential agents in the pipeline continues to steadily expand (see Table 3.1). If we conduct business as usual with intermediate-sized phase II clinical trials with a single agent compared to placebo, then we face very inefficient means to evaluate and identify the most promising candidates and may never reach a definitive answer. In addition, we may need to revisit the primary end point utilized for most studies to date. Current practice uses the change in β-cell function over time, which often requires close observation over a 12- to 24-month period and is an indirect measure of the inciting autoimmune response. Thus, study design may need to be refocused on testing a series of agents, utilizing a common control group; where possible, study design may adopt surrogate immune markers that will allow a faster readout of promising agents that should be further evaluated.59 If appropriate surrogate measures can be identified, an adaptive design may achieve this. Study size, study power, and effect size will also need to be addressed. For drugs with greater risk, one may want to demand a higher effect size, in order to consider the attendant risk acceptable. For a drug with no or minimal risk, one may be willing to accept a much smaller effect size. Greatest interest will be placed in those drugs that appear to have a tolerizing effect.

Furthermore, many now feel that the most successful approaches will require targeting more than one pathway in order to interdict this complex process of autoimmune destruction, much as has been necessary with organ transplantation and cancer therapy.60,61 Targeting multiple pathways with two (or more) drugs poses considerable hurdles, including the following considerations:

  • What is the best combination?
  • What is the ideal dose and length of therapy for each component of the cocktail?
  • What is the ideal timing for each agent relative to the others to be utilized?
  • Could there be additive or synergistic toxicities that could result from the combination, such as an infectious disease risk from immunosuppression?
  • For trial design, should there be arms to evaluate each therapy alone and then the combination, vs. a placebo, or is combination vs. placebo adequate?
  • Will industry be willing to partner with investigators and other companies to evaluate combination therapies, or might they remain risk averse and avoid such trials in order to limit any potential for uncovering new toxicities with an emerging therapy?
  • Will the investigators be able to work with the FDA to settle the associated regulatory and ethical concerns that such combination therapies will pose for T1D, in which evolving clinical therapies continue to improve over time?

DCMS155CG

These are clearly formidable hurdles to anticipate and overcome, and yet some combination trials have already been completed, such as the unsuccessful attempt with mycophenolate mofetil plus daclizumab (NCT00100178), the trial in Brazil with ATG, GCSF, and Cyclophosphamide, and the ongoing trial with sitagliptin plus lansoprozole (NCT01155284).41,62,63 Furthermore, one should bear in mind that some single agents such as monoclonal antibodies are quite precise and focused in their target, whereas other monotherapies are more multifaceted, targeting multiple sites or multiple cell types, such as ATG, which cross-reacts with multiple cell surface T-cell antigens. Another example is a tyrosine kinase inhibitor, imatinib, which will soon be evaluated in a phase II new-onset T1D trial. This drug targets multiple tyrosine kinases, in a variety of cell types, but this broader targeting may be necessary to quell the autoimmune response in T1D.

There is ongoing discussion about the ideal drug combination for such a new-onset T1D trial. General guidelines have been suggested in an ITN-JDRF assessment group, including:

  • Initially assessing combination therapies in preclinical models
  • Limiting initial combination studies to two drugs at first
  • Giving priority toward drugs that have already shown some level of efficacy and safety in T1D trials as a monotherapy and to FDA-approved drugs
  • Selecting drugs that operate via independent and complementary mechanisms
  • Paying attention to safety, with sequential rather than simultaneous use of the drugs, if possible60

One cocktail now being explored further is with anti-CD3 mAb plus IL-1 β blockade (canakinumab). Data is available for each drug alone in new-onset T1D trials, and there is a larger safety experience from which to draw. Preclinical studies are promising with this combination, and the drugs have complementary effects, targeting both innate and adaptive immunity. Another natural combination under consideration is coupling anti-CD3 mAb to antigen-based–therapy in order to extend the benefits of initial immune modulation, and it appears promising in animal models. Drugs that may enhance β-cell repair or regeneration, such as GLP-1 agonists or DPP-IV inhibitors, may also serve well in combination with an immunomodulatory agent. As the list of completed clinical trials with a single agent in new-onset T1D grows, many promising potential combinations will no doubt continue to emerge.

Eligibility Criteria

New-onset studies have typically targeted subjects shortly after diagnosis, and indeed studies such as the cyclosporine trials and the recent Protégé trial with teplizumab suggest that those who enrolled earlier had better responses. However, several investigators are exploring that assumption further, to determine if there is a broader window than may have been previously appreciated in which interventions may be helpful. As metabolic control has improved and as investigators have evaluated subjects at various times from diagnosis, a substantial portion retain clinically significant amounts of stimulated C-peptide (i.e., above the 0.2 pmol/ml threshold established in the DCCT). A phase II trial with teplizumab for subjects 4–12 months from diagnosis noted a trend toward β-cell preservation 1 year later, though the effects do not appear as robust as those noted for newer onset subjects (NCT00378508).64 Several early trials, in phase I or phase I/II, are now enrolling T1D subjects up to 2 years out from diagnosis. These are studies in which there is a focus on safety, with an attempt to get an early assessment of efficacy (NCT01106157, NCT01210664). If this window for possible therapy can be broadened from the usual study window of less than 3 months from diagnosis, then investigators will be able to enroll clinical trials more rapidly. As they are approved, there may ultimately be a broader target population for effective therapies.

As noted above, there is an ongoing challenge of how to best transition clinical trials into younger age-groups. Drugs are primarily studied in adult patients, to gain initial experience to prove safety and possibly efficacy, before exposing children to a potentially harmful drug. This approach poses several possible constraints from a clinical trials perspective. First, the disease process itself may be somewhat different in an older population than in children: the rate of β-cell decline following T1D diagnosis is faster in those aged 21 years 65 and findings from several recent trials indicate that younger children may be more likely to respond to therapies than older participants (Herold, Lancet 2012, submitted).2,54

Standardize Approach to Trials and Reporting of Trials Outcomes

Ultimately, investigators will need to compare results from different agents from various clinical trials and determine which agents should be pursued further in larger phase III studies alone or in combination with other drugs. As has been suggested by others, in order to advance the field, it will be extremely helpful if key aspects of the study design and data analysis are conducted in similar fashion.66,67 To a large extent, TrialNet and the Immune Tolerance Network have adopted very similar approaches, and many others are now doing so as well. There have been extensive past discussions about the choice of primary outcome to document preservation of endogenous β-cell function, and many agree with stimulated C-peptide, such as obtained with a mixed-meal tolerance test.67 Some studies have utilized or are considering a composite end point, such as A1C and exogenous insulin use that may reflect endogenous insulin secretion.2 A group of common secondary metabolic measures may also be helpful to include in all trials, such as exogenous insulin use, severe hypoglycemia, and A1C. For presentation of results, some common reported analysis will be helpful, such as for mixed-meal tolerance test providing 2- and 4-h C-peptide area under the curve as well as peak C-peptide; a shared definition of responder vs. nonresponder; similar approach on handling missing tests in the analysis (imputation or not); and how to handle results that are at the lower limit of detection (zero versus input one half the lower limit of detection).

IV. CONCLUSION

Current clinical therapy for T1D is suboptimal: the majority of patients are not able to consistently meet necessary glycemic targets to avoid long-term complications. Investigators now have the means to screen and identify those at risk for T1D, and a series of primary and secondary prevention trials offer promise for blocking progression to overt disease. For those with recent-onset T1D, several immunomodulatory agents have been found to delay β-cell destruction, and a series of intriguing trials are underway or are being planned. Ultimately, combination therapy, using complementary and synergistic agents, may be necessary to interdict the autoimmune process. New strategies are needed to more efficiently evaluate the emerging pipeline of therapies for both T1D prevention and β-cell preservation.

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