Antigen-Specific Immunotherapy for Type 1 Diabetes: Maximizing the Potential:

Posted on November 2, 2010

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Antigen-Specific Immunotherapy for Type 1 Diabetes: Maximizing the Potential :

September 2010

The identification and study of autoimmune diseases has taught us that recognition of self-antigens can have devastating consequences. Yet there is a paradox to autoreactivity: when correctly balanced, it is at the heart of robust self-tolerance. This concept gives rise to several questions. Can this balance be manipulated? And if so, by what means and through which mechanisms? What are the rules that govern this opportunity to restore homeostasis?

Studies in a variety of animal models, which act as replicas of the major chronic inflammatory diseases that affect humans, have offered many answers to these questions. One of the clearer outcomes is that delivery of autoantigens, administered at different disease stages via a variety of routes, can provide robust, sustained health and protection from inflammatory autoimmune disease. The most appealing element to this approach, termed antigen-specific immunotherapy (ASI), has been that it not only provides an effective means of controlling the autoimmune response via induction or restoration of β-cell–specific tolerance, but that it may achieve these goals without major concerns over safety and certainly without the specter of immune suppression. Yet significant questions remain. Are we doing enough to realize the potential of this sacred cow? How do we move from concept to reality?

The Current Clinical Trial Landscape in Type 1 Diabetes: A Question of Balance

Given the many potential advantages of ASI over non-ASI discussed heretofore (safety, prospect of tolerance, site-specific regulation), it might be expected that clinical strategies based around antigens would be pursued vigorously and in many quarters. Paradoxically, however, this is far from being the case (Fig. 2). A snapshot view of major studies (as opposed to small-scale pilots) that have been completed and published, are currently in progress, or are at an advanced stage of planning indicates that at the stages of disease that are often referred to as primary and secondary prevention, ASI is indeed the dominant modality under investigation. However, there is much more clinical trial activity in the intervention arena (i.e., tertiary prevention, very close to diagnosis), and many more of the agents under evaluation are non-ASIs, especially when one considers the trials that are currently active. In general the ASI studies are low-risk and dominated by a single antigen, insulin. There is a sense that the desire to conduct studies in the prevention arena has led to trials of the very safest of drugs (e.g., injectable insulin), but these trials have not necessarily been fully optimized for efficacy.

Figure 2.
Schematic representation of the balance of clinical trial activity in type 1 diabetes. Data are modeled onto a graphical representation of diabetes progression (adapted from reference;[38] reprinted with permission from Atkinson). Data are separated in two dimensions. First, according to stage of disease (primary prevention in the genetically at-risk before autoimmunity is apparent; secondary prevention when autoimmunity is present but no disease; and tertiary prevention or intervention when diabetes has been diagnosed but there is the opportunity to preserve C-peptide secretion); second, according to whether the therapy is antigen-specific (in black) or nonantigen-specific (in red). Underlined therapies are currently actively recruiting. The pie charts indicate the relative proportions of antigen-specific (black) and nonantigen-specific immunotherapy (red) in use at the different disease stages. DIPP, Diabetes Prediction and Prevention;[39] APL, altered peptide ligand;[40] ATG, anti-thymocyte globulin; CTLA-4Ig, cytotoxic T lymphocyte antigen-4 immunoglobulin; GCSF, granulocyte colony stimulating factor; HSCT, hematopoietic stem cell transplant; IFA, incomplete Freund’s adjuvant; IL-1β, interleukin-1β; MMF/DZB, mycophenolate mofetil and daclizumab;[41] α1-AT, α-1 antitrypsin; PBMC, peripheral blood mononuclear cell; TNF-α, tumor necrosis factor-α.
Figure 2.

Schematic representation of the balance of clinical trial activity in type 1 diabetes. Data are modeled onto a graphical representation of diabetes progression (adapted from reference;[38] reprinted with permission from Atkinson). Data are separated in two dimensions. First, according to stage of disease (primary prevention in the genetically at-risk before autoimmunity is apparent; secondary prevention when autoimmunity is present but no disease; and tertiary prevention or intervention when diabetes has been diagnosed but there is the opportunity to preserve C-peptide secretion); second, according to whether the therapy is antigen-specific (in black) or nonantigen-specific (in red). Underlined therapies are currently actively recruiting. The pie charts indicate the relative proportions of antigen-specific (black) and nonantigen-specific immunotherapy (red) in use at the different disease stages. DIPP, Diabetes Prediction and Prevention;[39] APL, altered peptide ligand;[40] ATG, anti-thymocyte globulin; CTLA-4Ig, cytotoxic T lymphocyte antigen-4 immunoglobulin; GCSF, granulocyte colony stimulating factor; HSCT, hematopoietic stem cell transplant; IFA, incomplete Freund’s adjuvant; IL-1β, interleukin-1β; MMF/DZB, mycophenolate mofetil and daclizumab;[41] α1-AT, α-1 antitrypsin; PBMC, peripheral blood mononuclear cell; TNF-α, tumor necrosis factor-α.
There are numerous explanations for this evident bias toward evaluation of novel non-ASI reagents at the intervention stage (Table 2).
Perhaps most worrying are 1) the limited involvement of the biotechnology and pharmaceutical industries in developing ASI and 2) the fact that assessing ASI at the intervention stage and expecting favorable metabolic outcomes in order that a full program of development can be progressed is a very hostile environment for these “weaker” therapies. The upshot is that this important treatment modality is not being evaluated in sufficient depth at the safest stage of disease (because the patients already have diabetes) when the acquisition of subjects is the least expensive (because screening is not required). Given that the collective ability to conduct rationally designed biomarker analyses has improved markedly in the last 10 years or so,[18] it would make sense for ASI to be evaluated in the intervention setting more on the basis of its effect on biomarkers than on metabolic outcomes.

Optimizing Antigen-specific Immunotherapy for the Clinic

Based on preclinical models, several factors are emerging as critical in determining the outcome of antigen-specific immunizations, most notably dose, route, adjuvant, and frequency of administration. Studies have shown that too frequent antigen administrations, as well as very high dosages, do not result in optimal induction of immune regulation and tolerance. In addition, there is no evidence that there is such a thing as “regulatory memory,” and in most prevention studies so far, repeated administration of the antigen has been required. Exceptions arise, for example when certain adjuvants such as alum or incomplete Freund’s adjuvant are used. Here, at least in animal models, a one-time administration of antigen with adjuvant is sufficient to prevent diabetes. In these cases, rather than augmentation of nTregs or de novo induction of iTregs or aTregs, an immune deviation to TH2 and induction of TH2 memory cells that produce IL-5, -4, and -13 might have occurred. This in itself might be very beneficial and the desired outcome of antigen-specific immunization in type 1 diabetes. We might not need to induce bona fide Tregs after all (i.e., the FoxP3+CD127lowCD25high type), but a mere TH2 deviation could be sufficient. IL-4 is exquisitely protective in various animal models for type 1 diabetes and has a large therapeutic range, especially when delivered locally to the pancreatic islets or lymph nodes via β-cell antigen–specific Tregs.[30] Thus, choosing the correct adjuvant (i.e., a TH2-deviating compound) might be the key to antigenic immunization and long-term tolerance in type 1 diabetes.[15] Tolerance-inducing adjuvants are not an area of large-scale research and are probably not in the development pipelines of many pharmaceutical companies.

In addition, several other factors need to be resolved. The most pressing issue is the precise dosing regimen. From the studies in various animal models, it is known that too high dosages might not be effective by leading to the deletion of Tregs rather than their augmentation. In murine models, for example, only oral insulin dosages between 0.2 and 2 mg are effective when given twice per week by oral gavage.[31] Higher and lower dosages have no strong effect on preventing diabetes, therefore there is a strong need to translate dose regimens used in these animal models to humans as accurately as possible. This has not been achieved to date, at least in part because there is no fully validated formula. However, the currently utilized 7.5-mg dose in the oral insulin study of Diabetes TrialNet, which mirrors that used in the Diabetes Prevention Trial (DPT)-1,[16] is most likely too low comparatively and, based on animal models, less frequent dosing with a higher dose should greatly increase efficacy. This factor could also explain the lack of efficacy in the Finnish nasal insulin diabetes prevention trial.[39]

New strategies and creative approaches will be required to more rationally and rapidly translate from mouse studies to human trials, as we will discuss in the next section.

http://www.medscape.com/viewarticle/727972

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