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

Ernesto Maddaloni¹, Rocco Amendolara¹, Angela Balena¹

¹Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Expert Opinion on Investigational Drugs

|March 1, 2024

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.

Insights

Researchers are exploring immune checkpoint pathways to treat type 1 diabetes (T1D). Targeting these pathways aims to dampen the immune response, offering a potential avenue for mitigating autoimmune diabetes and improving T1D outcomes.

Area of Science:

Immunology
Endocrinology
Autoimmunity

Background:

Type 1 diabetes (T1D) significantly impacts quality of life and life expectancy despite insulin therapy advancements.
The immune system's role in T1D pathogenesis involves a loss of self-tolerance.
Immune checkpoint signaling pathways, crucial in cancer immunotherapy, are being investigated for autoimmune diseases.

Purpose of the Study:

To review cellular and molecular mechanisms underlying loss of immunological tolerance in T1D.
To examine the role of immune checkpoint molecules in T1D development.
To assess the potential of immune checkpoint modulation for treating autoimmune diabetes.

Main Methods:

Comprehensive literature review of T1D pathophysiology.
Analysis of preclinical and clinical studies on immune checkpoint modulators.
Evaluation of evidence regarding immune checkpoint molecules in T1D.

Main Results:

Conflicting results exist regarding the efficacy of immune checkpoint modulators for T1D.
Few molecules studied in preclinical settings are suitable for human trials.
The complex and heterogeneous nature of T1D pathophysiology may contribute to varied outcomes.

Conclusions:

Immune checkpoint modulation holds promise for T1D, but challenges remain.
Future clinical trials must account for T1D's complexity, potentially requiring multi-pathway approaches.
Careful trial design is essential to harness the therapeutic potential of these compounds for autoimmune diabetes.

Read full analysis

Keywords:

Type 1 diabetes abatacept autoimmunity belatacept immune checkpoints immune intervention prevention

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