“The daily trial of insulin injections could soon be over for hundreds of thousands of people with type-1 diabetes,” is the overoptimistic headline in The Times.
A small study involving immune “T-reg cells” proved safe for participants, but it is far too early to talk about an end to daily injections.
In type 1 diabetes the body’s immune cells attack the insulin-producing beta cells in the pancreas. Without the hormone insulin, people with type 1 diabetes can’t control the levels of sugar in their blood.
High levels of sugar (hyperglycaemia) can damage the blood vessels and nerves, while low levels (hypoglycaemia) can cause unconsciousness. Most people with type 1 diabetes need to inject insulin regularly.
It was already known that people with type 1 diabetes have fewer cells called T-regulators (T-regs), which are involved in stopping the immune system attacking healthy cells such as beta cells. Now a group of scientists has found a way to take T-regs from people’s blood, filter out any defective cells, and expand the numbers of healthy T-regs so they can inject them back.
This study was to test whether the technique is safe, rather than effective. The researchers say they can’t tell from the varied responses of the 14 people in the study whether the treatment actually helped preserve insulin production, let alone restore it.
Where did the story come from?
The study was carried out by researchers from the University of California, Benaroya Research Institute in Seattle, Yale University and KineMed Inc.
It was funded by the Juvenile Diabetes Research Foundation International, the Brehm Coalition, the Immune Tolerance Network, BD Biosciences and Caladrius Biosciences.
The study was published in the peer-reviewed journal Science Translational Medicine. Unsurprisingly, several of the study authors hold patents for the therapy or have been paid by companies interested in providing it.
The reporting in both The Times and The Daily Telegraph made it sound as if the treatment had been shown to work and was ready to be rolled out, when this is far from the case.
The coverage in The Independent and Mail Online was more cautious, sticking mainly to the facts about the study.
What kind of research was this?
This was a phase 1 dose-escalation safety trial. Phase 1 trials are designed to look at safety, not effectiveness.
In this case, the trial was carried out to see whether patients with diabetes could tolerate the treatment without it causing severe side effects. Larger efficacy trials are done after safety trials to limit the number of people affected if they do find dangerous side effects.
What did the research involve?
Researchers recruited 16 adults who had recently been diagnosed with type 1 diabetes and took a large sample of blood from them.
They separated out the T-reg cells, removed defective cells, and treated the T-regs to expand their numbers. They then infused the T-reg cells back into the bloodstream, and followed these people up to see what happened.
Two of the recruits did not have their cells transfused back into their bodies, as when researchers tested the samples, they failed to meet pre-set safety criteria. The researchers tested the function of the T-regs before they infused them back into the 14 remaining people.
The treatments were done in stages, one group of people at a time, with the first group receiving the smallest dose of T-regs. The researchers waited at least 13 weeks to see if anyone in the first group got serious side effects before moving on to give a bigger dose to the second group, and then repeating the process.
People had weekly follow-up visits to check for side effects for the first four weeks, then every 13 weeks for the first year, with regular checks until five years after treatment. They also had a number of tests before and after treatment to see whether they were producing insulin.
What were the basic results?
Nobody in the study had serious side effects the researchers thought had been caused by the treatment. This is important, because immune cell therapy could potentially cause problems, such as a severe reaction to the infusion.
There is also the potential risk of a cytokine release, when T-cells produce proteins called cytokines that cause severe inflammation, similar to that of a bad infection.
Nobody in the study had either of these problems, and none of the participants suffered from an increase in infections, which was also a potential side effect if there are more cells that dampen the immune response.
The main adverse events experienced by people in the study were episodes of very high or very low blood sugar, which happens in people with diabetes when blood sugar is uncontrolled. The researchers say these were unlikely to be linked to the therapy.
Follow-up studies showed some of the T-reg cells remained in the bloodstream for a year after infusion, although most of the cells (about 75%) could no longer be found 90 days after treatment.
Studies of the treated T-regs in the laboratory, before they were infused back into people, showed the cells seemed to have recovered their ability to prevent the body from wrongly attacking beta cells. However, we don’t know if this ability persisted after they had been injected.
Tests of a protein called C-peptide, which can indicate whether people are producing insulin, showed a range of results. In some people, the levels remained about the same as before treatment, when you would normally expect them to decline over time.
In other people, the levels of C-peptide dropped off to nearly zero after a year. The researchers say that, given the small numbers of people in the study and the fact they’d been treated at different times in the progression of the disease, it was impossible to tell whether the treatment had made any difference to these results.
How did the researchers interpret the results?
The researchers concluded that their results “support the development of a phase 2 trial to test efficacy of the T-reg therapy”.
They say their therapy, when combined with other treatments being developed, “may lead to durable remission and tolerance in this disease setting”.
These early-stage results show work is underway to find a long-term treatment for type 1 diabetes, which could one day mean people do not have to inject insulin.
However, that day is a long way off. Headlines suggesting an end to daily injections can unfairly raise people’s hopes, leading to disappointment when no such treatment emerges.
Bringing a new treatment into use requires at least three stages of trials, from the phase 1 safety trials, to phase 2 studies of efficacy, to larger-scale phase 3 clinical trials, where the treatment is given to large groups of people who may be followed-up for some time.
This is usually done with a comparison group to see whether the new treatment performs better than placebo or the established treatment. Many treatments get no further than phase 1.
The results from this study are encouraging for the researchers, as they allow them to move on to the next phase of study. However, it doesn’t mean there are no safety concerns.
We need to see whether the treatment is safe and effective when given to large groups of people. Only after successful phase 3 trials can people with type 1 diabetes start to hope for an injection-free future.