Type 1 Diabetes Vaccine One Step Closer

Instead of suppressing the immune system, this new approach engages it

With Bart Roep PhD and Lawrence Steinman MD

If approved, the new type 1 diabetes vaccine would only need to be injected once.

An innovative vaccine that uses a person's own immune cells and vitamin D to treat type 1 diabetes has proven safe and feasible, according to preliminary research.

"This is a completely, radically new strategy," say Bart Roep, PhD, director of The Wanek Family Project for Type 1 Diabetes and the Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes at the City of Hope in Duarte, California. "Instead of suppressing the immune system, we are engaging it.

The strategy acts as an ''inverse vaccine," Dr. Roep says, in that it will stop, rather than activate, specific immune responses.

The vaccine was tested at the Leiden University Medical Center in the Netherlands in a first-in-human phase I clinical trial in 9 patients with long-standing type 1 diabetes. "They'd had it about 13 years and were in their mid-20's at the time of the study," Dr. Roep tells Endocrine Web.

"We think this approach could be useful in established disease," he says. "Many type 1 diabetes patients still have some beta cells left. It's not game over."

Study details

According to Dr. Roep, inducing or restoring immune tolerance is the ''holy grail" in type 1 diabetes.''

However, he says, non-specific immunotherapies to control the T-cell dependent autoimmune response show substantial side-effects and only modulate the course of the disease temporarily, as his own research has found.

His aim is to selectively target and regulate beta-cell autoimmunity. He says that tolerogenic dendritic cells (tolDCs) are viewed as an attractive approach to modulate autoimmune disease in an antigen-specific way to intervene in the pathogenesis of type 1 diabetes.

For the trial, he took a patient's immune cells and manipulated them in a lab to become anti-inflammatory. Next, they loaded cells with a fragment of insulin-producing beta cells from the pancreatic islets and added vitamin D. The vitamin D helped train the immune system to modulate inflammation, Dr. Roep says.

They then injected these modified immune cells back into the patients. He used proinsulin peptide loaded tolDCs in the patient.

(Naturally derived proinsulin peptide C19-A3 is safe, others have shown. It's also been shown to elicit immune responses in those with type 1 diabetes, and tolDCs presenting the peptide can induce proinsulin specific regulatory T-cells.)

The tolDCs pulsed with proinsulin peptide were given by two intradermal vaccination series, a month apart (saline injections were also given). Doses were 5, 10, or 20 million tolDCs per injection.

According to Dr. Roep, ''That the vaccine is safe and feasible is important because we have basically injected beta cell protein, the target of the autoimmune response that causes type 1 diabetes in an attempt to make the immune system ignore it." The goal was to stop the attack on the insulin-producing cells.

After injection, the patients were monitored for 6 months. They compared reactions with the injections and also with saline injections. There was mild stinging and redness of the skin at the injection site. The skin reactions disappeared within two weeks and didn't need additional care. 

During the six months, B-cell function and overall control of diabetes was stable, Dr. Roep found. Patients maintained tight glycemic control. Insulin requirements were unchanged.

Weakly hypoglycemic events were similar to before the trial.

Of the 9, 3 patients had detectable stimulated C-peptide that did not change after treatment. This low rate of residual B-cell function was expected, with the safety-driven strategy.

No signs of immune suppression systemically were evident, Dr. Roep says.

Next, Dr. Roep says he wants to study the approach in those with a shorter time from diagnosis, such as patients diagnosed one to five years earlier, who have many more beta cells that could be preserved and protected. He is planning to do that trial, also a phase 1.

He is hopeful that the vaccine may eventually help prevent complications such as neuropathy and blindness.

And, he writes: "Further testing would tell whether antigen-specific immunomodulation using tolDCs protects B cells from autoimmune destruction and can act as curative therapy for type 1 diabetes."

The current study was supported by the European Union, the Dutch Diabetes Research Foundation, and the DON Foundation.

Expert perspective

"The use of a cellular therapy as an inverse vaccine is a major potential advance in therapy for type 1 diabetes," says Lawrence Steinman, MD, the Zimmermann Professor of Pediatrics, Neurology and Neurological Sciences at the Beckman Center for Molecular Medicine at Stanford University. He reviewed the study results, but was not involved in this research. He and Dr. Roep collaborate on another approach for type 1 diabetes using a DNA-based inverse vaccine.

Instead of targeting the immune system with treatment that suppresses it, "Roep aimed to dial back autoimmunity to proinsulin," Dr. Steinman says. "To accomplish this, he used a special cell, the dendritic cell. He put vitamin D in his chemistry recipe for cultivating these special cells so that they would turn down the unwanted immune response to proinsulin seen in Type 1 diabetes."

Dr. Steinman says the initial results, although studied in a small group, "appear promising."

He and his colleagues studied a similar approach, reporting last year about an inverse vaccine for multiple sclerosis, produced by giving the tolerizing dendritic cells chemical fragments of the myelin sheath.

In that study, including 12 patients (8 with MS and 4 with neuromyelitis optica spectrum disorders), Dr. Steinman and his colleagues tested increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4 (aquaporin-4). They found that the therapy was well tolerated, without serious adverse events and with no therapy-related reactions. In the phase Ib trial, they found an increase in IL-10 levels in PBMCs stimulated with the peptides, as well as an increase in the frequency of a regulatory T cell by week 12.

More from Dr. Roep

Asked how often such a vaccine would be needed, if research bears out, Dr. Roep tells Endocrine Web, "My hope and expectation is that if we do it right, it should be sufficient to only inject once." 

Dr. Roep and Dr. Steinman have no other relevant disclosures.

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