In people with type 1 diabetes (T1D), the immune system destroys the insulin-producing cells in the pancreas, leading to high blood glucose levels, which are deadly if left untreated. All people with type 1 diabetes rely on insulin injections or infusions to regulate their blood glucose levels. Individual insulin requirements are affected by many factors and tailoring the dosing regimen around the clock requires a lot of mental effort, with many patients finding it difficult to consistently achieve their target ranges.

The search for better clinical approaches for type 1 diabetes is ongoing, with many labs around the world focusing on better treatments and the ever-elusive “diabetes cure”. Most recently, researchers at the City of Hope described the first-ever human phase I clinical trial of a “inverse vaccine” to treat type 1 diabetes patients.

We previously reported on this novel potential treatment approach when it was still in its pre-clinical stages at the ADA Scientific Sessions last June. Now, we have reconnected with the lead researcher, Dr. Bart Roep, Ph.D., the Chan Soon-Shiong Shapiro Distinguished Chair in Diabetes at City of Hope and director of The Wanek Family Project for Type 1 Diabetes, to learn about the outcomes of the first-ever human trial.

What Is an “Inverse Vaccine”?

When we think of a vaccine in a traditional sense, we are usually referring to the stimulation of the immune system to develop an immunity and prevent illness from a particular microbe. An “inverse vaccine”, on the other hand, is designed to stop a specific immune response (e.g., the unwanted autoimmune response that destroys beta cells in patients with type 1 diabetes).

How Does the Treatment Work?

This treatment aims to retrain the patient’s immune system to self-tolerate the insulin-producing beta cells in the pancreas. First, specific immune cells (called dendritic cells, DCs) are collected from the patient’s blood and are specifically treated, in particular, with pro-insulin peptide and vitamin D. When the stimulated cells are injected back into the patients, in a series of “vaccinations”, they can elicit a specific subset of the patient’s T cells (regulatory T cells, or Tregs), which should, in turn, act to regulate the unwanted autoimmune response seen in type 1 diabetes.

Dr. Roep explained more:

“We want to negotiate with the immune system rather than bombard it into submission, because the latter may affect your chances of fighting off cancer and infections, including coronavirus.”

First Clinical Trial Results Show Promise

The novel vaccine was recently tested to assess safety and tolerability in nine patients with type 1 diabetes of long duration (at baseline, only three patients had detectable C-peptide levels, indicating some degree of insulin production). The results of the study were just published last week.

The treatment “passed the test” with respect to serious adverse events. The researchers describe that,

“Most importantly, there were no signs of systemic immune suppression, no induction of allergy to insulin, no interference with insulin therapy, and no accelerated loss in beta-cell function in patients with the remaining C-peptide. In conclusion, generation and intradermal administration of [the treatment] appears feasible and safe.”

Clinicians monitored various other health parameters throughout the trial, including glycemic management, which remained stable for all participants. Notably, Dr. Roep stated that,

“With regard to the unexpected clinical benefits: while we told the participating patients that it was a safety and feasibility trial, they have all-time low HbA1c years after our therapy (long after the trial ended) and on average, 13 years after their diagnosis. This is bizarre, and could point to beta-cell regeneration (perhaps once you stop the immune attack) or possibly waking up hibernating beta cells that came out of hiding after the immune system got back in check. Speculation, of course, but tantalizing observation nonetheless, in the preferred direction.”

Why were patients with long-standing diabetes selected for this initial investigation? Dr. Roep explained:

“There are two reasons why we involved patients with long-term disease.

First, to build-in extra safety precautions in this first in-human trial, we selected patients with long-term disease whose condition is less likely to worsen. After all, we injected a vaccine built on their pancreatic islets, so in theory, this could aggravate islet autoimmunity.

The other reason is a frustration that I share with my stakeholders, the diabetes patients: all efforts to intervene in the disease are biased toward a short period after diagnosis. We just learned that most patients keep beta cells for most of their lives, so it is worth protecting those beta cells and serving patients with longstanding T1D at the same time. Our novel strategy is also perfectly suited to do so: perhaps it is even smarter to negotiate with the immune system once the medical emergency is over and remaining beta cells (and the immune system) get some rest. All other strategies so far bombarded the immune system into submission; this big hammer is probably better justified early on.”

You can read even more about the study, including the patient selection process and the specific treatment protocol here.

What’s Next?

Based on the success of the phase I trial that evaluated the safety and tolerability, the research group expect to conduct more human testing:

“Our results warrant subsequent clinical testing in patients with a shorter diagnosis of type 1 diabetes and with preserved C-peptide production, to assess whether this novel immune intervention strategy is able to delay or halt progressive loss of beta-cell function. Further testing would tell whether [the treatment] protects beta cells from autoimmune destruction and can act as curative therapy for type 1 diabetes.”

Dr.  Roep and colleagues are optimistic about the future:

“Our research brings us one step closer to finding a vaccine against type 1 diabetes, an ambitious quest at City of Hope, and the hope of many patients with this disease.”

Of course, there is a long road ahead before we can know for sure whether this type of therapy will be truly effective. Moreover, the way that type 1 diabetes develops differs between patients, and it is likely that immunotherapies will have to be tailored to different patient subsets, as we previously discussed with Dr. Roep.

Nevertheless, such a tailored approach constitutes a previously unexplored form of treatment for type 1 diabetes patients, which could lead to effective therapies, and perhaps even a cure. We will continue to follow this research and provide updates as more research is conducted.

Read the official press release about this clinical trial from the City of Hope here.

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