Treg Therapy Found Safe, Effective at Slowing ALS in Small Trial

Treating patients with their own immune regulatory T-cells (Tregs), in combination with IL-2 — a protein that boosts the cells’ immunosuppressive function and survival — is generally safe and shows potential to slow disease progression in people with amyotrophic lateral sclerosis (ALS).

That’s according to a small Phase 2a clinical trial (NCT04055623), whose data also suggested that levels of inflammatory and oxidative stress markers may help predict patients’ response to treatment. Oxidative stress is a type of cellular damage implicated in ALS.

These promising early findings call for larger trials to confirm this approach’s therapeutic potential in people with ALS, the researchers noted.

The results were detailed in a study, “Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis,” published in the journal Neurology: Neuroimmunology and NeuroInflammation.

What are regulatory T-cells (Tregs)?

Tregs are a type of immune cell that typically dampens excessive inflammatory responses, thereby helping to maintain a healthy immune balance.

Previous research has shown that ALS is associated with a shift toward an increase in pro-inflammatory immune T-cells to the detriment of Tregs. Also, the remaining Tregs are dysfunctional, and their abnormalities are linked to disease progression rate and severity.

This suggests that boosting Treg numbers and function may slow ALS progression and lessen disease severity.

To explore this hypothesis, researchers at Houston Methodist Neurological Institute conducted a pilot, open-label Phase 1 trial (NCT03241784), in which three ALS patients were administered Tregs directly into their bloodstream.

Tregs were collected and isolated from each patient’s own blood and expanded in the lab in the presence of IL-2, a molecule essential for their survival and immunosuppressive function. The cells, with a restored immunosuppressive function, were then infused back into the patient.

Each patient received a total of eight infusions of Tregs over about six months, in addition to under-the-skin injections of IL-2 three times a week.

Results showed that this approach had a favorable safety profile and was associated with increased Treg suppressive function and numbers, as well as a slower disease progression.

Later analyses, supported also by Coya Therapeutics, demonstrated that this positive response was accompanied by a reduction in the levels of inflammatory and oxidative stress markers.

Of note, Coya has licensed Houston’s Treg manufacturing process and is developing a Treg-based therapy for ALS called COYA 101, formerly known as ALS001. The treatment has received orphan drug designation in the U.S., which is meant to accelerate its clinical development and regulatory review.

These positive findings supported the launch of a Phase 2a trial to confirm the therapeutic benefits of this Treg-based approach in a larger number of patients. The study — funded by the ALS Association, ALS Finding a Cure, and the Muscular Dystrophy Association — was conducted at Houston Methodist Hospital and Massachusetts General Hospital.

While the trial was expected to enroll 12 patients, “the COVID-19 pandemic limited the enrollment to 9 participants,” the researchers wrote, adding that Tregs from two of these patients could not be expanded.

As such, seven participants (six men and one woman; mean age 49.8 years) were randomly assigned to receive monthly infusions of either their own Tregs (1 million cells/kg) or a placebo, in addition to IL-2 injections three times a week, for six months.

Six participants completed this period, while one in the placebo group discontinued the study due to an allergic reaction after the second infusion.

What were the findings of the open-label phase?

The six participants, in addition to two additional men with ALS (mean age 68 years), entered the study’s open-label (OLE) phase, in which all received ascending doses of Tregs plus IL-2 for six months.

In the OLE, patients first received two infusions of 1 million Tregs per kg of body weight, which were then followed by two infusions of 2 million cells/kg and two infusions of 3 million cells/kg. IL-2 injections were donated by Clinigen, which is developing a lab-made version of IL-2, called aldesleukin, as a potential therapy for ALS.

The trial’s main goal was to assess changes in Treg function at six months, while secondary goals included safety measures and changes in Treg numbers. Changes in disease progression, lung function, and blood levels of inflammation and oxidative stress markers were evaluated as exploratory outcomes. Not all lung function assessments were completed due to the COVID-19 pandemic.

Results at six months showed that Treg suppressive function was reduced by 6.4% in the placebo group and increased by 20% in the Treg/IL-2 group, reflecting a 26.4% difference between the groups. This difference failed to reach statistical significance, likely due to the smaller number of patients enrolled, the team noted.

However, patients receiving the therapy experienced a significant increase in Treg suppressive function at week 34 (about eight months) and week 42 (about 9.5 months) in the OLE phase.

Treg counts in the blood were also higher than at the study’s start (baseline) during the OLE, meeting statistical significance at 34 weeks.

In addition, six of the eight OLE participants showed slow to no disease progression, as assessed with the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised. While these scores typically decline at a rate of one point per month, these patients experienced an average decline of 2.7 points over the six months — or 0.45 points per month.

In turn, one patient from each group of the placebo-controlled phase showed rapid disease progression throughout the trial, with a total decline of 10.5 points over the six months, or 1.75 points per month.

These two fast-progressing patients were found to have higher levels of two pro-inflammatory markers, IL-17F and IL-17C, and of two oxidative stress markers, OLR1 and ox-LDL, than patients with intermediate to no progression — whose levels were within or close to the normal range.

The findings suggest that these pro-inflammatory and oxidative markers may be used to predict responses to this approach and assess whether changing its frequency or dose may help improve treatment response in this specific subgroup of patients, the team noted.

The Treg/IL-2 therapy was generally safe and well-tolerated, with mild adverse events and no major differences in the adverse event profiles between groups. Mild and temporary inflammation at the site of IL-2 injections were common.

The trial’s placebo-controlled phase “was limited by the small number of participants and the fact that the COVID-19 pandemic precluded reaching the planned number of enrollments as well as the completion of several clinical assessments,” the researchers wrote.

“A larger clinical trial would allow for the proper evaluation of clinical efficacy and further characterization of the long-term safety of this therapy,” they concluded.