Although ALS is a neurodegenerative disease, researchers are increasingly also interested in events happening outside the brain and spinal cord, in particular whether changes in the immune system might play a role in influencing the course of the disease. This is a subject we’ve covered before, with particular reference to the ongoing MIROCALS drug trial of interleukin-2 (IL-2), see blog post here.
Today, some of the work that has supported the MIROCALS (Modifying Immune Responses and Outcomes in ALS) trial has been published in Lancet EBiomedicine by a consortium of clinical and laboratory scientists from France, UK, Italy, and Sweden. The paper reports results from the pilot IMODALS (Immune Modulation in ALS) trial of low dose IL-2.
Although the cause of ALS is not fully understood, it is known that inflammatory mechanisms influence motor neuron damage in the brain and spinal cord. A type of white blood cell called regulatory T cells (Tregs) are known to contribute to the control of this inflammatory response.
Tregs play an essential role in our immune system and are dependent on IL-2 for survival and function. At low doses, as used in IMODALS, IL-2 is well tolerated and has been shown to increase Treg numbers and function in the blood.
The IMODALS study had three main goals,” said lead investigator, Prof Gilbert Bensimon, of the University Hospital of Nimes, France.“The first goal was to show that low doses of IL-2 amplify Treg numbers and function in ALS patients and that any change seen was related to the dose of the drug.
The third goal required regular blood sampling over the three-month period of the trial to measure the numbers, function, and types of Tregs and other circulating immune cells. This also allowed the researchers to test the hypothesis that low dose IL-2 should alter the levels of specific chemical messengers known to be key players in the immune system, as well as looking at markers of nerve cell damage in ALS.
The double-blinded study involved 36 people with ALS, who were randomly assigned to three groups of 12 participants. Each group received either one of two doses of IL-2, or placebo (a dummy drug), by an injection under the skin, over five days every month, for three months. As changes to the immune system can be long lasting, the clinical safety observations continued for a further three months.
The main findings were that low dose IL-2 significantly increased the numbers of circulating Tregs, as predicted, and – importantly – improved their ability to control other immune cell responses that contribute to nerve cell damage.
This double benefit of ‘more Tregs’ and ‘better Tregs’ indicates that low dose IL-2 therapy is fully functional in ALS patients” said Dr Tim Tree, an immunologist at King’s College London, who was involved in key parts of the laboratory analysis. “Furthermore, this response was related to the dose of IL-2, with higher levels of Tregs in the participants who received the higher dose.”
Importantly, IL-2 was safe and well tolerated by the ALS trial participants. “This is a drug that is used in much higher doses to treat some rare forms of cancer and it can have severe side effects, but we did not see these occurring in the lower doses used in this study” said Prof Bensimon.
More encouraging indications were found in the measurement of changes in blood cytokines and chemokines (cell signalling molecules that aid cell to cell communication in immune responses), which were in keeping with the notion that low dose IL-2 reduces the harmful effects and enhances the beneficial effects of immune activity in the nervous system in ALS.
Overall, these findings strongly support further investigation of IL-2 in ALS and have provided crucial insights for the ongoing MIROCALS trial which seeks to detect improvement in day-to-day activity and survival in ALS over a much longer 18-month trial period and is scheduled to finish towards the end of 2021.
Update 14/07/20: The lab-made version of low-dose interleukin-2 (Aldesleukin) earns FDA’s Orphan Drug Designation as ALS Treatment: alsnewstoday.com/clinigens-aldesleukin-earns-fdas-orphan-drug-designation-as-als-treatment/
Reference to the published paper: Camu, W., Mickunas, M., Veyrune, J.-L., Payan, C., Garlanda, C., Locati, M., Juntas-Morales, R., Pageot, N., Malaspina, A., Andreasson, U., Kirby, J., Suehs, C., Saker, S., Masseguin, C., Vos, J.D., Zetterberg, H., Shaw, P.J., Al-Chalabi, A., Leigh, P.N., Tree, T. and Bensimon, G. (2020). Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial. EBioMedicine. https://doi.org/10.1016/j.ebiom.2020.102844
Further information on MIROCALS can be found at: