Immune checkpoint modulators in early clinical development for the treatment of type 1 diabetes

ABSTRACT

Introduction

Despite the improvements of insulin therapy, people with type 1 diabetes (T1D) still suffer from a decreased quality of life and life expectancy. The search toward a cure for T1D is therefore still a scorching open field of research.

Areas covered

Tackling the immune checkpoint signaling pathways has gained importance in the field of cancer immunotherapy. The same pathways can be targeted in autoimmunity with an opposite principle: to dampen the exaggerated immune response. In this review, we report a comprehensive excursus on the cellular and molecular mechanisms that lead to loss of immunological tolerance, and recent evidence on the role of immune checkpoint molecules in the development of T1D and their potential application for the mitigation of autoimmune diabetes.

Expert opinion

Contrasting results about the efficacy of immune checkpoint modulators for T1D have been published, with very few molecules from preclinical studies eligible for use in humans. The heterogeneous and complex pathophysiology of T1D may explain the conflicting evidence. Designing clinical trials that acknowledge the pathophysiological and clinical complexity of T1D and that forecast the need of simultaneously tackling different disease pathways will be crucial to enhance the benefits which may be gained by such compounds.

KEYWORDS:

• Type 1 diabetes
• immune checkpoints
• immune intervention
• autoimmunity
• abatacept
• belatacept
• prevention

Article highlights

• The loss of immune tolerance against self-antigens and the cytotoxic response against beta cells are two key moments characterizing the immune dysregulation of type 1 diabetes (T1D). Immune checkpoints are molecules expressed on the surface of immune cells, with the main role to prevent the activation of immune responses against self-antigens.

• Although on the one hand T1D is a severe side effect of immune checkpoints inhibitors, the modulation of the same pathways may be used to induce or restore immune tolerance against beta cells or to turn off the autoimmune insulitis in affected people.

• Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is an immune checkpoint molecule with inhibitory effects on the activity of cytotoxic T-cells. It is the target of abatacept and belatacept, the only two drugs modulating immune checkpoints’ pathways which have been tested in clinical trials of T1D.

• Studies conducted so far suggest that abatacept may slow down the rate of beta cell loss in people with T1D. However, abatacept was not superior to placebo in preventing the progression of T1D from phase 1 to phase 2.

• Many other compounds, acting on co-inhibitory (PD-1/PD-L1, TIM, LAG3) and co-stimulatory (CD40-CD49L, OX40, ICOS, 4-1BB) pathways, are being tested in animal models of autoimmune diabetes. Data available so far from such studies seems to suggest that some benefits might be gained by tackling immune checkpoints’ pathways in T1D.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed they work for Novonordisk, who are involved in developing immune therapies for T1D. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.