Therapies to Alter the Course of Type 1 Diabetes and Achieve a Cure: Exploring Diverse Pathways

To best meet the expectations of our readers, we asked our subscribers to choose the topic they were most interested in regarding immunology. This article therefore addresses one of the most popular questions. You can also find our two other articles from our special coverage of the IDS, available freely and also translated into English: “Beyond Autoantibodies: How to Optimize Type 1 Diabetes Screening?” and “Type 1 Diabetes Cure: What Can We Expect from Immunology Specialists?”.

But how can we talk about diabetes immunotherapies in 2024 without first mentioning the only treatment currently in use, which is almost exclusively used across the Atlantic: Teplizumab? A necessary starting point to understand the role this type of molecule will play in a future of T1D without insulin, it is the flagship of so-called "disease-modifying" therapies. Approved in November 2022 by the FDA (Food and Drug Administration), this monoclonal antibody partially alters autoimmunity in people at stage 2, presymptomatic stage of the disease, to delay the onset of clinical diagnosis, or stage 3.

Before delving into other potential therapies for the future, it is important to remind that even Teplizumab, approved for clinical use in only a handful of countries around the world, is still finding its footing. Studies continue to explore how best to administer it, as well as whether it can be used at earlier or later stages than its current prescription. This is the focus of the discussion led by Pierre Lemaitre, Clinical and Experimental Endocrinology Researcher at the Catholic University of Louvain in Belgium.

For the Belgian scientist, understanding the mechanisms of resistance and responses to immunotherapies is essential in adapting each therapy to individual patients. He highlights how certain biomarkers, such as neutrophils—white blood cells with various roles—can provide insight into the proper functioning of an immunomodulator like Teplizumab: "The genes expressed by neutrophils often reflect the inflammatory environment of the pancreas and can predict the effectiveness of therapies." By extension, a better response to treatment, as shown in mouse models, will result in better preservation of insulin-producing beta cells. The Louvain researcher believes that “understanding their role could be the key to transforming our therapeutic approach”. He hopes to use these biomarkers to guide clinical trials and better target the patients who could benefit from specific drugs. This would also have the positive effect of reducing the cost and duration of clinical trials.

Following Pierre Lemaitre, Dr. Courtney Crane, Vice President of the biotech company Mozart Therapeutics, took the stage to present their work on the MTX-101 molecule, clearly stating their goal to "restore immune balance without widespread immunosuppression, paving the way for safer and more effective treatments”. MTX-101 targets CD8 regulatory T cells (Tregs) to treat T1D. In doing so, it limits the proliferation of autoimmune CD4 T cells that attack the beta cells of the pancreas while avoiding side effects involving other immune cells. Encouraging results have been observed both in vitro and ex vivo, showing a reduction in inflammation, a decrease in beta cell destruction, and an increase in insulin secretion. In clinical trials with healthy adults, the molecule showed a favorable safety profile and will soon be tested on T1D patients to assess its effectiveness.

Meanwhile, Lindsay Pallo, a PhD student at the University of British Columbia in Vancouver, presented the concept of an mRNA vaccine that could prevent or reverse T1D. Containing both immunomodulators to reduce the inflammation caused by traditional mRNA vaccines and adapted antigens, this vaccine is distinguished by the encapsulation of its material with lipid nanoparticles (LNP). Its action aims to reintroduce immune tolerance toward beta cells by facilitating integration by dendritic cells, which are involved in triggering immune responses. Results from both prevention and reversal of hyperglycemia in diabetic mice demonstrated the establishment of an immune-tolerant environment, allowing for a return to normal blood glucose levels for up to 150 days after vaccination.

Another session focused on the dialogue between beta cells and immune cells featured the intervention of biologist Erica Cai from the Indiana Biosciences Research Institute. A specialist in the protection of pancreatic beta cells, the researcher presented her findings in understanding the ZBED3 gene and its role in their ability to survive and remain resilient against autoimmunity. This gene was identified by Erica Cai's team as playing a role in the beta cells' propensity to trigger autoimmunity. By modifying or inhibiting this gene, beta cells become less visible to T cells and therefore survive better against their attacks, while also secreting insulin more effectively. The potential impact of this discovery for future functional treatments is clear. Erica Cai emphasized the importance of advancing this research to better "understand these mechanisms and design beta cells that are resistant to autoimmune attacks, which would be a crucial step toward reversing type 1 diabetes," particularly in the case of islet transplantation.

The IDS conference also featured an exciting intervention from American physician and researcher Denise Faustman. A professor of medicine at Harvard University, she discussed the significant role that the well-established Bacillus Calmette–Guérin (BCG) tuberculosis vaccine could play in T1D. The vaccine helps modify immune responses and impacts lymphoid cells within the immune system. Faustman considers it a serious candidate for treating T1D in people who have been living with the disease for many years. It would require multiple doses and a relatively long time to impact the metabolism of immune cells, as it "does not only act directly on the pancreas, but induces a systemic transformation that takes time to establish”. However, its results are surprising. Long-term chronic patients experience a significant reduction in their glycated hemoglobin levels without their beta cell function being restored, "thanks to a metabolic reorientation of their lymphoid system," according to Faustman. She concluded on the topic of a functional cure, expressing hope to "combine BCG with therapies such as islet transplants to maximize the immunological and metabolic benefits”.

Rheumatoid arthritis, multiple sclerosis, vitiligo, and type 1 diabetes: the study of autoimmune diseases reveals numerous similarities in terms of inflammation, fibrosis, and biomarkers of disease progression. This is the observation made by Professor of Rheumatology at the University of Michigan, David Fox, who encourages “leveraging successes in other diseases to design more effective treatments for type 1 diabetes”. Taking the example of the autoimmune attack by cytotoxic T cells common to both vitiligo and T1D, he emphasizes the potential benefit for T1D of the anti-IL-15 treatment, already used in vitiligo. Similarly, he discusses the role of anti-CD6, which has proven effective in multiple sclerosis to reduce immune responses, and suggests it could also be valuable in treating T1D. Lastly, referring to biomarkers identified in rheumatoid arthritis that have enabled the recognition of distinct genetic profiles among patients, facilitating more personalized therapeutic strategies, Professor Fox asserts: “They can become key tools for selecting patients likely to respond to a specific therapy, thereby improving clinical outcomes.”

Rare genetic diseases, resulting from monogenic mutations, are another valuable source of knowledge to improve the understanding of the fundamental mechanisms of T1D progression and the development of potential treatments. This is the contribution of immunology and genetics expert Professor Mark Anderson from the University of California, San Francisco. According to him, “observing patients with monogenic mutations allows us to understand how a single gene can cause a major immune disruption”. A notable clinical case is that of a T1D teenager carrying a STAT1 mutation, who experienced total remission of his diabetes after being treated with ruxolitinib. This JAK inhibitor restored immune tolerance toward beta cells, thus completely reversing the diabetes. The treatment allowed to “stop insulin therapy and maintain HbA1c within a non-diabetic range”.

Inflammatory bowel diseases, such as Crohn’s disease or ulcerative colitis, also serve as possible references for understanding the mechanisms of T1D and potential treatments. The dysfunctional immune response, along with the high increase of these chronic diseases in Western countries, makes the link with T1D quite apparent. However, as demonstrated by Séverine Vermeire from the Catholic University of Leuven, a professor specializing in gastrointestinal disorders research, there are challenges and setbacks alongside the successes in the field. While the genetic mapping of these diseases has shed light on their biological mechanisms, the Belgian researcher also highlights progress in treatment with anti-TNF agents like infliximab. At the same time, she points out the limited success, as “only 30% of patients achieve durable remission, far from the progress observed in dermatology for psoriasis”. Furthermore, she notes the discrepancies between clinical exam results and patient reports, where “only one-third of those with normal mucosa report normalization of their symptoms”: thus, the criteria for treatment success should also be questioned, as well as the still underexplored aspects of the microbiome and diet as triggers and progress factors for these diseases, as is the case for T1D.

Invited as a rising star in research, Zoe Quandt, an endocrinologist at the University of California, San Francisco, shared a specific case linking cancer treatment with T1D. Indeed, the American researcher demonstrated the paradoxical impact of certain immunotherapies that, while highly effective against various types of cancer, can potentially trigger autoimmune diseases. These therapies, by utilizing immune checkpoint inhibitors to destroy cancer cells, can induce T1D as a side effect. “These therapies are revolutionizing cancer treatment, but they also trigger autoimmune disorders affecting nearly all organs, including the pancreas,” explained Zoe Quandt. She emphasized the severity of this immunotherapy-induced diabetes, often accompanied by ketoacidosis in 50 to 75% of cases, and characterized by targeted destruction of beta cells without generalized inflammation of the pancreatic islets. Unlike classic T1D, these cases occur without the usual autoantibodies. She also mentioned an intriguing observation: patients developing this form of diabetes appear to respond better to cancer treatments and enjoy prolonged survival, revealing a complex and still poorly understood link between these conditions. This paradoxical connection between therapeutic success against cancer and autoimmune disease remains a mechanism that must be studied in-depth to be fully understood.

The IDS congress again proved to be a platform for numerous scientific sessions showcasing the richness and dynamism of research worldwide. These sessions demonstrated that while immunotherapies are still in their infancy in the field T1D, they are already finding effective models elsewhere. This suggests the potential for future optimizations in patient treatments, in all their diversity. It fuels growing impatience within the patient community and their loved ones for a future that may be less burdensome and perhaps even without insulin.

This article is part of a three-part series on the Immunology of Diabetes Society Congress. To ensure free access to this content, the series is funded by IDS. Glucose toujours retains full editorial independence.

Translation reviewed by Anna Jones