Research Spotlight: Advances in Immunotherapy for Type 1 Diabetes

The most common treatment for type 1 diabetes (T1D) is insulin for the improvement of symptoms associated with high blood glucose levels. However, the underlying cause of T1D, which involves damage to the insulin-producing pancreatic beta cells, remains unresolved. This damage is caused by the body’s immune response, which goes into overdrive and attempts to eliminate beta cells — even though these cells are part of the body. A major player in this autoimmune response is a group of immune cells called T-cells. This is why the immune system, including the T-cells, is an obvious target to manage the underlying cause of T1D.

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No immunotherapies have been approved for T1D, but a few are in development. Let’s look at some of these immunotherapies and their potential benefit for T1D patients.

Antibodies

Inhibition of the attacking T-cells may help protect beta cells, and so antibodies can be used to target and inhibit these T-cells. For example, antibodies that target a molecule called CD3 are being developed for T1D treatment. These antibodies bind to CD3 and prevent CD3-mediated activation of T-cells. One such anti-CD3 antibody is teplizumab, which has been shown to preserve beta-cell function in people with T1D. Furthermore, in a recent study, it delayed the onset of T1D in high-risk individuals. This observation highlights its potential as a preventative treatment.

Other potential antibodies for T1D therapy are antibodies that act against interleukin-1 and tumor necrosis factor-alpha (TNF-α), which are signaling molecules involved in inflammation and destruction of beta cells. Antibodies against these molecules may benefit T1D, since clinical studies have shown that inhibition of these molecules improve beta-cell preservation.

Therapies that induce immune-suppressing T-cells

Beta cells can be protected from the autoimmune response via the presence of regulatory T-cells, which are immune-suppressive cells. Various strategies are being explored to increase the number of these cells in the pancreas, including the use of anti-CD3 antibodies and a signaling molecule called interleukin-2 (IL-2).

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Vaccines

Beta-cell damage can be prevented if the attacking T-cells are tolerant toward the beta cells. This tolerance may be increased by exposing T-cells to a small amount of specific proteins (or parts of proteins called peptides) from beta cells. A peptide called C19-A2 proinsulin has been shown to regulate the immune response mediated by certain T-cells. Furthermore, this peptide was found to improve beta-cell function in individuals newly diagnosed with T1D.

ActoBio Therapeutics is developing an oral capsule (AG019) that delivers human proinsulin and a tolerance-inducing molecule called interleukin-10 to the lining of the stomach and intestines. This capsule contains a genetically engineered bacterium called Lactococcus lactis, which expresses these molecules so they can be delivered to the target region. In preclinical studies, this therapy in combination with an anti-CD3 antibody reversed T1D in 89% of mice with early-stage T1D. The company has now initiated a phase 1/2 trial to evaluate this drug in newly diagnosed individuals with T1D.

Immune cell therapy

Administration of certain immunomodulatory cells may help alleviate the aggressive immune response against beta cells. A group of cells called tolerogenic dendritic cells are known to suppress the immune response through various mechanisms. Administration of these cells, along with regulatory T-cells, is being explored as a potential strategy to prevent or reduce beta-cell destruction by the immune system.

Another new approach is to develop regulatory T-cells expressing certain receptors that enable the cells to specifically target the pancreatic beta cells (CAR-T cells). This could increase the effectiveness of the therapy while reducing any unwanted effects of the cells at other non-target regions of the body.

Overcoming immunotherapy challenges

Although various immunotherapies are being explored for T1D treatment, several challenges need to be addressed. The factors involved in T1D vary among individuals with this condition. This makes treatment complicated, as one type of therapy might not be effective for all individuals. For example, not all individuals with T1D have inflammation in the islet cells. Therefore, therapies aimed at reducing inflammation in the islet cells might not benefit patients who do not have this type of inflammation. Considering the individual variation in T1D characteristics, the use of personalized medicine may be the most beneficial approach.

Another challenge in T1D immunotherapy is achieving favorable efficacy. Targeting the immune system may generate a wide variety of responses, which could reduce efficacy of treatment and produce side effects. Physicians and researchers are attempting to tackle this problem through combination therapies. Combining therapies that act through different mechanisms of action improves the effectiveness of treatment. Combinations need to be decided in such a manner that efficacy is improved and side effects reduced.

The future

Although we have a long way to go, new directions in T1D immunotherapy show much promise for individuals with T1D. In the future, we may even be able to use immunotherapy to prevent the condition before it manifests. This strategy is possible because we now have the technical ability to identify individuals at risk of T1D before the occurrence of any major damage to the beta cells.

Want to learn more about type 1 diabetes? Read “Type 1 Diabetes Questions and Answers,” “Six Type 1 Diabetes Symptoms You Need to Know” and see our type 1 diabetes videos.

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