The MIROCALS trial and beyond
by Ms. Pippa Pringuer and Dr. Chien-Hsiung (Alan) Yu
One in 10,000 Australians will be diagnosed with MND in their lifetime, and this number is projected to increase with time. Unfortunately, we do not yet have an effective therapy that is able to stop or slow down progression of the disease.
Abnormal build-up of proteins is a common feature across neurodegenerative diseases, including MND. This build-up of protein is associated with the death of motor neurons in the brain and spinal cord (known collectively as the central nervous system or CNS), which can impair our ability to move, swallow, breathe and speak. At present, scientists and neurologists are working together to understand how these harmful processes are triggered, in order to catch and treat the disease early enough to halt its progression.
Our immune system generates inflammatory responses that work to fight infection and maintain tissue health through coordination between multiple types of immune cells. These cells can promote and control inflammation in a ‘seesaw’ fashion to ensure sufficient defence against disease-causing agents, as well as to protect our body from excessive inflammation – not too little, not too much, but JUST RIGHT. Importantly, dysregulation of these immune responses can play a key role in damaging the health and function of motor neurons in MND. Therefore, modulating our immune system to avoid these disease-causing processes could provide a new therapeutic strategy for MND.
Figure 1. Degenerating motor neurons in Motor Neurone Disease.
Using stem cell technology, scientists are now able to make motor neurons in a dish to study the biology of MND and treatment efficacy in humans. This image shows degeneration of motor neurons, as indicated by broken neuronal structure. (Cyan – cell nucleus; Magenta – neuronal axon; Yellow – motor neurone marker).
Image provided by Dr. Alan Yu.
The clinical trial, “Modifying Immune Response and Outcomes in ALS” (MIROCALS), extended the use of Interleukin-2 (IL-2), a molecule involved in control and modulation of immune responses, in large-scale groups of patients with MND. Previous studies have shown that low-doses of IL-2 were well-tolerated, and increased the number and function of Regulatory T cells (Tregs) in the blood of MND patients. These immune cells play an important role in controlling systematic inflammation by suppressing other cells in the immune system. For this reason, this new phase II trial was designed to validate the effectiveness and safety of low-dosage IL-2 in MND patients shortly after their diagnosis. Participants were randomly assigned to a group that received IL-2 or a group that took a placebo tablet. The participants and the researchers were not told who received IL-2 and who received the placebo. The study went for 18-months, with 220 patients recruited from clinics across France and the United Kingdom. To assess the effect of IL-2 treatment, a range of outcomes, including survival time and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score, were compared between the treatment and placebo-control groups. The primary analysis of survival showed an overall 19% decrease in the risk of death in those who received IL-2, a finding which was not statistically significant.
Participants who took part in the trial had highly variable symptoms and this can make it difficult to measure the effect of new treatments on symptom severity and the speed of progression. To this end, the MIROCALS trial also evaluated levels of phosphorylated neurofilament heavy chain (pNFH) in the cerebrospinal fluid (CSF - fluid that flows around the brain and spinal cord), which is a known brain biomarker for MND and other neurodegenerative diseases. When neurons become damaged or die, the building blocks of these neurons can begin to fall apart into fragments (Figure 1), which can be released into the CSF, or even the bloodstream. Measuring the pNFH building block in the CSF is therefore a useful measure of neurodegeneration, and was used in this study to control for disease severity. The MIROCALS trial found a significant 40% decrease in the risk of death in those with low to moderate pNFH levels, corresponding to mild disease progression. No significant treatment effect could be detected in rapidly progressive patients with high pNFH levels. Overall, this first large-scale IL-2 trial delivered a proof-of-concept that neuroinflammation can be targeted by inducing Treg activation as a treatment option to reduce the risk of death in early-stage patients.
Despite the promising results of this study, there remain many considerations to address in evaluation of the applicability of IL-2 or Treg activation as a treatment for MND. It is known that IL-2 can activate not only Tregs but also other T cell populations that can cause inflammation and death of cells in the circulation. The neuroprotective effects observed in this trial by IL-2 treatment or Treg activation in the peripheral system remain to be investigated in detail. On the other hand, over-activation of Tregs may increase the risk of infection in the peripheral immune system, as these cells are involved in suppression of the immune response. Additional analyses of IL-2 treatment would be required to further assess the potential risks associated with this treatment. Furthermore, many studies have suggested differences in the mechanisms and nature of immune regulation in peripheral immune system compared to local cells in the CNS. Treg activation is likely a secondary, or even further downstream, immune effect. More significant effects may be observed by targeting primary responses in order to effectively slow or halt disease development. Therefore, it is worth questioning how effective it is to target regulatory T cells, which are involved in dampening peripheral immune responses, to treat inflammation in the brain and spinal cord.
Dr Alan Yu is Head of the Neuroinflammation Laboratory at The Florey Institute.
The MIROCALS trial provides encouraging data, and has helped to advance our new therapeutic strategies by aiming to intervene in the onset and progression of MND. Indeed, recent discoveries from our group, and others, have demonstrated exciting preclinical potential therapeutics that block immune processes in the brain or spinal cord for new treatments of MND. Notably, existing biomarkers which occur upon death of neurons, including pNFH used in this trial, do not sufficiently catch disease development early enough and are not specific to MND. We suggest that these cell signalling pathways in the CNS should continue to be assessed for new diagnostic biomarkers occurring before the death of neurons, to help detect and treat MND at the earliest possible timepoint.
The journey towards finding real cures and treatments is still challenging, as MND is a complex disorder with unknown causes and many triggers. Nevertheless, more and more interdisciplinary research programs have been established, bringing together the expertise of biomedical and clinical scientists, industrial partners, and patients, families, and carers. Use of this collective knowledge will continue to enable new discoveries, advancement of our understanding of the biology of this devastating condition, and new treatments and technologies which will be available to the medical and patient community. Support of innovative ideas and early- and mid-career researchers (EMCR) will remarkedly speed up the hunt for a cure, as exploration into new therapeutic targets allows us to see light at the end of the tunnel.
Dr Alan Yu is Head of the Neuroinflammation Laboratory at The Florey Institute. Dr Yu studies the inner workings of the innate immune systems including how they function against infection. His research investigates the molecular events behind the immune-mediated neurodegenerative pathway in MND. His work has been recognised internationally and he continues to secure grants to progress research into MND.