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Increasing the number and function of a certain type of white blood cell and returning them to the same patient may slow progression of the degenerative disease amyotrophic lateral sclerosis (ALS), an early study suggests.

The phase IIa trial indicated that infusions of autologous, expanded regulatory T-lymphocytes (Tregs) increased their immunosuppressive function in ALS patients when used together with low-dose interleukin (IL)-2, which helps regulate the immune system’s white blood cells.

Acknowledging the challenges of running their small study during to the COVID-19 pandemic, the researchers nonetheless note that taking Tregs from patients, increasing their numbers in a lab, then returning them back to the same patient was safe and well tolerated.

“We look forward to a much larger clinical trial that will allow for proper evaluation of clinical efficacy and further characterization of the long-term safety of this therapy,” said its principal investigator Jason Thonhoff, from Houston Methodist Neurological Institute in Texas. “These early results in a handful of patients are promising.”

The research is published in the journal Neurology: Neuroimmunology and Neuroinflammation.

The trial was originally designed as a randomized, placebo-controlled, phase IIa trial with 12 participants who had the rare neurological disease, which would be followed by an open-label trial.

But the impact of the coronavirus pandemic led to reduced enrolment, with seven participants ultimately in the double-blind trial and eight in the six-month open label trial.

The first, six-month part was designed to examine the biological activity, safety, and tolerability of intravenous monthly expanded Tregs (1 x 106 cells/kg) or inactive saline placebo administered intravenously plus injections of subcutaneous low-dose IL-2 (2 × 105 IU/m2) or saline placebo three times per week.

Six of the original trial participants proceeded into the second, six-month dose-escalation open-label extension, with two additional patients joining.

Participants received a single dose of Treg cells twice, at a frequency of  once per month with three IL-2 injections per week, followed by double, then triple the dose of Treg cells twice, with IL-2 injection, all at the same frequency.

This was followed by a one-month, follow-up safety visit after the last triple dose of Tregs and IL-2 injections.

The researchers note that, due to the low pandemic enrolment, the study had limited power to detect the trial’s primary and secondary endpoint.

Nevertheless, the trial’s primary endpoint of change in Treg suppressive function from screening to week 24 of treatment was 26 per cent higher in participants receiving Treg/IL-2 compared with placebo.

During the trial active treatment was well tolerated, with only mild adverse events and mild and transient inflammation at IL-2 injection sites common.

The researchers note that the single anaphylactic reaction with placebo has previously been observed in other studies using vehicles containing albumin or dimethyl sulfoxide.

A post-hoc analysis of the extension study showed six of the eight participants experienced intermediate to no disease progression, whereas the remaining two showed rapid progression while receiving the Treg/IL-2 treatment.

Six of eight participants in the open-label extension changed by an average of −2.7 points per the ALS Functional Rating Scale–Revised, whereas the other two changed by an average of −10.5 points.

The two progressing patients had higher levels of proinflammatory IL-17F and IL-17C cytokines as well as higher oxidative stress markers OLR1 and ox-LDL than the other six.

The researchers say: “The high levels of inflammation and oxidative stress observed in these two participants could have limited the effectiveness of the Tregs resulting in shorter half-lives and negating their downstream suppressive effects.”

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