International Alliance of ALS/MND Associations

T Regulatory Cell Therapies

Background

Neuroinflammation was discovered many years ago to be a key contributor to the degeneration of motor neurons in ALS/MND. Cells called microglia that surround motor neurons and provide immune protection to a healthy central nervous system, lose some of their normal function while becoming abnormally activated, secreting substances that likely increase motor neuron damage. Other cells, called T cells, travel in the bloodstream and are capable of exiting into the area near motor neurons, where they can play a neuroinflammatory role. Through studying the aspects of T cells in ALS/MND more closely it was discovered that certain types of T cells, called regulatory T cells (Tregs), can also be protective and naturally reduce these neuroinflammatory effects. Furthermore, the level of effective Tregs is lower in people with ALS/MND and the amount of Tregs is correlated with rate of disease progression (ie. more in slower progressors, less in fast). As a result, treatment strategies attempting to increase the body’s production of Tregs or to provide more of them have been advanced to clinical trial in recent years. A number of trials are examining regulatory T cells as a primary means of treating ALS/MND or as a contributor to a treatment strategy.

These include:

  1. Dr. Stanley Appel’s regulatory T cell transplants and Coya Therapeutics –Dr. Appel is the initial champion for the potential in targeting Tregs as a treatment for ALS/MND, including founding research over a decade ago that demonstrated their protective effects in mouse models. In this treatment regimen, Tregs are removed from blood (a process called leukapheresis), multiplied in number outside the body (in a lab), and returned intravenously (IV) along with a subcutaneous low dose of a substance called interleukin-2 (IL-2), which helps stabilize the Tregs.
    • Coya 101
      • An initial clinical trial of Treg treatment in three individuals demonstrated very intriguing results (1) that warranted a phase 2 trial in 7 participants. It is important to note that the first trial was extremely small so interpretation of effect cannot be made at this point. The phase 2 trial looked at a combined treatment of Tregs and IL-2 and was a double-blind, placebo-controlled trial to primarily assess safety and effect on immune and inflammatory ALS/MND effects. There was a six month open label extension for all participants after six months of study during which they found that Treg/IL-2 was safe and well tolerated and increased the function of Tregs in people with ALS/MND but not the numbers (results published here). A larger trial is needed to assess whether Treg/IL-2 treatment can slow disease progression.
    • Coya 302
      • A small trial of a combination of IL-2 and CTLA4-Ig (a protein designed to decrease the activity of immune cells that promote inflammation) was
        conducted in 4 participants. The trial involved treatment with Coya 302 for a total of 48 weeks. It was found to be safe and well tolerated with no
        serious side effects. Increased Treg activity and a decrease of other markers of inflammation were found during treatment, but these effects wore off once treatment stopped. The results also suggested a transient and minimal change in ALSFRS-R score, as a measure of disease progression, throughout the study. Due to the small size of the trial, a larger placebo-controlled phase 2 trial is needed to continue testing whether this could be beneficial for ALS/MND.
  2. RAPA-501 Therapy – Rapa Therapeutics conducted an open label phase 1 trial of RAPA-501 T cells where T cells were removed from blood, treated outside the body (in a lab) with substances to both increaseTreg activity and reduce other inflammatory cell activity, followed by IV reintroduction of the cells to the participant with or without a regimen (called PC regimen) designed to assist in the Rapa T cell effectiveness. This trial aimed to establish safety and an effective dose to use. This phase 1 trial has led to a further phase 2/3 open label trial of RAPA-501 where all participants will receive treatment with RAPA 501. This is currently underway and assessing the safety of the highest dose and effectiveness on T cells function.
  3. Rapamycin (RAP-ALS) – An academic phase 2 trial at eight sites in Italy studied the effects of oral rapamycin on ALS/MND over 18 weeks of treatment, followed by 36 months of follow up. Rapamycin is thought to both increase Treg cell number as well as help autophagic degradation of various aggregate-prone proteins. The trial in 63 people analysed levels of biomarkers and other key metrics of how the treatment acts in the body. The primary goal of the trial was to measure Treg levels. The trial found that some people on the treatment had an increase in numbers of Tregs compared to those on placebo but the difference was not statistically significant. It was also found that it may help to decrease inflammation but further studies are needed to fully assess the effects on Tregs and better understand how rapamycin works in the body (published here).
  4. MIROCALS Trial – A joint academic effort between UK and French researchers, the Modifying Immune Response and OutComes in ALS (MIROCALS) trial examined low dose IL-2 alone over 18 months to determine if it is sufficient to enhance a person’s own Tregs. This was a large trial that recruited 220 people across 17 clinics and participants were studied over 18 months for an effect on disease progression and survival. The study was formally published in The Lancet in May 2025 as a phase 2b randomized, placebo-controlled trial (Bensimon et al., 2025). Initial results were presented at the International Symposium in December 2022.In 2025, detailed analyses confirmed that IL-2 at a low dose was safe and well tolerated, consistent with the early findings. The primary endpoint of overall survival was assessed over a 21-month follow-up period.Side effects were minimal across both treatment and placebo. The adverse-event profile was consistent with expectations; most events were mild and transient, including local injection site reactions and transient flu-like symptoms.

    The primary endpoint (measure) for the trial was survival. The ‘raw analysis’ of the results showed only a modest and non-significant decrease in the risk of death in those who received IL-2 compared to the placebo at the end of the trial. Specifically, the unadjusted hazard ratio for death was 0.81 (p = 0.33), showing no significant difference between treatment arms. However, additional statistical modeling, adjusted for baseline phosphorylated neurofilament heavy chain (pNfH) levels in cerebrospinal fluid—a biomarker of disease aggressiveness—revealed a survival benefit in participants with lower or moderate pNfH concentrations (hazard ratio 0.52, p = 0.016).

    In contrast, individuals with high baseline pNfH levels, corresponding to a more aggressive disease course, did not show any treatment benefit (hazard ratio 1.37, p = 0.38). These subgroup findings highlight the prognostic and predictive role of neurofilament biomarkers in ALS/MND clinical trials.

    ALS/MND symptoms did continue to progress in both the placebo and IL-2 group, which resulted in people dying at a similar rate in both groups. Nonetheless, low-dose IL-2 induced apparent biological effects, including a robust and sustained expansion of regulatory T cells (p < 0.0001) and a reduction in plasma chemokine CCL2 concentrations, indicating targeted immunomodulation.

    The published findings suggest that IL-2 may confer clinical benefit for a biomarker-defined subgroup of patients with slower disease progression, supporting the rationale for confirmatory trials focused on this population. Notably, Treg numbers were increased in those receiving IL-2 vs. placebo, both in this study and a prior, preliminary study called IMODALS.

    Together, IMODALS and MIROCALS demonstrate that low-dose IL-2 safely engages its intended immunological target; however, it is not an effective treatment for all individuals living with ALS/MND. The findings suggest that low-dose IL-2 may have disease-modifying potential within a biomarker-defined subgroup of people with ALS/MND (Bensimon et al., 2025).

  5. Nebulized RNS60 –Revalesio Corporation tested an inhaled experimental drug  that contains oxygenated nanobubbles called RNS60, and has demonstrated  anti-inflammatory and neuroprotective effects in preclinical ALS/MND models. One of  the effects demonstrated in mice was an increase in Tregs. A small investigator initiated, open label, pilot trial has previously established safety and tolerability  (2). RNS60 was tested in a phase 2 clinical trial of 147 participants and markers  of inflammation were measured. The trial found no difference in these markers  between those on RNS60 and those on placebo, suggesting that it did not have  an effect on the immune system or Tregs. However, it was found to have some  benefit in slowing decline in respiratory and bulbar functions (e.g. swallowing  and talking) (published here). Further trials of RNS60 are needed to continue to  investigate these effects.

Recommendation

The Scientific Advisory Council (SAC) recommends that caution be taken in interpreting the effectiveness of the different approaches targeting regulatory T cells as a treatment for ALS/MND. While promising preclinical science and clinical trial data exists in small study samples, it is too early to know if any of these strategies are truly effective. Each of these are exciting in their possibilities for treating ALS/MND and the SAC looks forward to learning more from rigorous studies in the time ahead.

International Alliance of ALS/MND Associations
March 2024 

The original language of communication is English and any translation cannot be guaranteed for accuracy of messaging.

SOURCES

Expanded autologous regulatory T-lymphocyte infusions in ALS | Neurology Neuroimmunology & Neuroinflammation

A Pilot Trial of RNS60 in Amyotrophic Lateral Sclerosis – PMC (nih.gov)