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T Regulatory Cell Therapies

Background

Neuroinflammation was discovered many years ago to be a key contributor to the degeneration of motor neurons in ALS. 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 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 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 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, 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 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 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.
  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 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. Although the results initially announced at the International Symposium in December 2022 were encouraging, results from the trial are not yet published. IL-2 was found to be safe and well tolerated. Side effects were minimal across both treatment and placebo. 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. However, when the analysis included a statistical adjustment, using neurofilament heavy chain (pNfH) levels as a way of predicting progression rate, the researchers found a statistically significant decrease in the risk of death for a subgroup of people in the trial with a less aggressive form of the disease. ALS symptoms did continue to progress in both the placebo and IL-2 group, which resulted in people still dying in both groups from their ALS. The results are preliminary and encouraging but further analysis of samples and data are ongoing that will answer crucial questions about the outcomes of the trial. Notably, Treg numbers were robustly increased in those receiving IL-2 vs. placebo, both in this study and a prior, preliminary study called IMODALS.
  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 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 SAC recommends that caution be taken in interpreting the effectiveness of the different approaches targeting regulatory T cells as a treatment for ALS. 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 and the SAC looks forward to learning more from rigorous studies in the time ahead.

References

1. Expanded autologous regulatory T-lymphocyte infusions in ALS | Neurology Neuroimmunology & Neuroinflammation
2. A Pilot Trial of RNS60 in Amyotrophic Lateral Sclerosis – PMC (nih.gov)

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.

Primary Sidebar

Drugs in Development

  • AB Science – Masitinib
  • BrainStorm Cell Therapeutics – NurOwn
  • Clene Nanomedicine – CNM-Au8
  • Collaborative Medicinal Development – CuATSM
  • ILB – Tikomed
  • Kadimastem – AstroRx
  • Methylcobalamin
  • Mitsubishi Tanabe Pharma America – Oral Edaravone
  • Neuronata-R/Lenzumestrocel
  • NeuroSense – PrimeC
  • Neuvivo – NP001
  • T Regulatory Cell Therapies
  • Prilenia Therapeutics – Pridopidine
  • SOD1 Therapies & Trials

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  • Horacio Fritzer, Argentina

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  • Brigitte Wernli,  Association ALS Switzerland,  Diagnosed 2014

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  • Ian Roberts

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  • Frank "Papa" Taylor

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  • Olga Cosentino, Diagnosed 2013,  Asociación ELA Argentina

    Olga Cosentino, Diagnosed 2013, Asociación ELA Argentina

  • Alan Liz Ogg 29042016 000799 lo res

    Alan Liz Ogg 29042016 000799 lo res

  • Natalya Rybakova, Russia

    Natalya Rybakova, Russia

  • Soledad Rodriguez, FUNDELA, Diagnosed 2013, Spain

    Soledad Rodriguez, FUNDELA, Diagnosed 2013, Spain

  • Natalya Rybakova, Russian Charity ALS Foundation

    Natalya Rybakova, Russian Charity ALS Foundation

  • Feng Gin Sun, Diagnosed 2014 , Shaanxi ALS Association, China

    Feng Gin Sun, Diagnosed 2014 , Shaanxi ALS Association, China

  • Wendy Hendrickson, ALS Hope Foundation, USA

    Wendy Hendrickson, ALS Hope Foundation, USA

  • Armando González Gómez, ACELA, Colombia

    Armando González Gómez, ACELA, Colombia

  • Lachlan Terry,  MND Australia,  Diagnosed 2015

    Lachlan Terry, MND Australia, Diagnosed 2015

  • Conny van der Meijden, Diagnosed 2001,  ALS Netherlands

    Conny van der Meijden, Diagnosed 2001, ALS Netherlands

  • Sam Hayden-Harler, Motor Neurone Disease (MND) Association, UK

    Sam Hayden-Harler, Motor Neurone Disease (MND) Association, UK

  • Alfredo Santos, Diagnosed 2013 , ACELA, Colombia

    Alfredo Santos, Diagnosed 2013 , ACELA, Colombia

  • Juvenal Bayona Romero

    Juvenal Bayona Romero

  • Josée Kolijn-de Man, Diagnosed 2015 , ALS Patients Connected, The Netherlands

    Josée Kolijn-de Man, Diagnosed 2015 , ALS Patients Connected, The Netherlands

  • Peng Yi-Wen

    Peng Yi-Wen

  • Sanjay Kumar Srivastava, Asha Ek Hope Foundation for ALS/MND, Diagnosed 2018, India

    Sanjay Kumar Srivastava, Asha Ek Hope Foundation for ALS/MND, Diagnosed 2018, India

  • Camilla Heiberg Freiberg, Muskelsvindfonden, Denmark

    Camilla Heiberg Freiberg, Muskelsvindfonden, Denmark

  • Eric Von Schaumburg, USA

    Eric Von Schaumburg, USA

  • Philip Brindle,  MND Association,  Diagnosed 2015,  England

    Philip Brindle, MND Association, Diagnosed 2015, England

  • Animesh Kumar, Diagnosed 2013 , Asha Ek Hope Foundation, India

    Animesh Kumar, Diagnosed 2013 , Asha Ek Hope Foundation, India

  • Diana Fernandez, Diagnosed 2009 , Asociación ELA Argentina

    Diana Fernandez, Diagnosed 2009 , Asociación ELA Argentina

  • Elisabeth Zahnd, Switzerland

    Elisabeth Zahnd, Switzerland

  • Michel Perrozzo, ARSLA, Diagnosed 2015, France

    Michel Perrozzo, ARSLA, Diagnosed 2015, France

  • Mike Small, Motor Neurone Disease (MND) Association, UK

    Mike Small, Motor Neurone Disease (MND) Association, UK

  • Shay Rishoni, Diagnosed 2011 , Prize4Life, Israel

    Shay Rishoni, Diagnosed 2011 , Prize4Life, Israel

  • Liam Dwyer, England

    Liam Dwyer, England

  • Bjarne Hytjanstorp, ALS Norge, Norway

    Bjarne Hytjanstorp, ALS Norge, Norway

  • Robbie Caliste, UK

    Robbie Caliste, UK

  • Duncan Bayly , MND Australia

    Duncan Bayly , MND Australia

  • Len Johnrose,  MND Association,  Diagnosed 2017,  England

    Len Johnrose, MND Association, Diagnosed 2017, England

  • Nicholas (Nic) Bowman, MND Association of South Africa,  Diagnosed 2016,  Australia

    Nicholas (Nic) Bowman, MND Association of South Africa, Diagnosed 2016, Australia

  • Karl Hughes, Diagnosed 2010 , IMNDA,  Ireland

    Karl Hughes, Diagnosed 2010 , IMNDA, Ireland

  • Alejandro Aquino, Diagnosed 2011 , Asociación ELA Argentina

    Alejandro Aquino, Diagnosed 2011 , Asociación ELA Argentina

  • Roxana Canova, Diagnosed 2012 ,  Asociación ELA Argentina

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  • Guoqiang Xu, Diagnosed 2016 , Shaanxi ALS Association, China

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  • Ian and Teresa Roberts

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  • Oliver Juenke, DGM, Germany

    Oliver Juenke, DGM, Germany

  • Graham Johnson, MND Australia

    Graham Johnson, MND Australia

  • Colm Francis Davis, Ireland

    Colm Francis Davis, Ireland

  • Art Eggert, USA

    Art Eggert, USA

  • Hans Dieter Olszewski, Diagnosed 2010 , DGM, Germany

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  • Mike Rannie,  ALS Canada,  Diagnosed 2017

    Mike Rannie, ALS Canada, Diagnosed 2017

  • Ana Lilia RodriguezApoyo Integral Gila A.C., Diagnosed 2018, Mexico

    Ana Lilia RodriguezApoyo Integral Gila A.C., Diagnosed 2018, Mexico

  • 83

    83

  • Andrea Zicchieri, Associazione conSLAncio Onlus, Italy

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