Fighting coronavirus with MSCs: an interview with Ross Macdonald

Ross Macdonald (Cynata, Melbourne, Australia) discusses the coronavirus outbreak following the news that mesenchymal stem cells (MSCs) had been successfully tested in a clinical trial in China.

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Following the news that mesenchymal stem cells (MSCs) were utilized in the treatment of COVID-19 complications, we sat down with Ross Macdonald (Cynata, Melbourne, Australia) to discuss the situation. This interview was originally recorded on 15 March 2020.  

Can you introduce yourself and tell us a bit about your role, please?
I'm Ross Macdonald, CEO of Cynata Therapeutics (Melbourne, Australia), which is a clinical-stage cell therapy company developing proprietary and unique manufacturing solutions for the production of therapeutic mesenchymal stem cells. MSCs are living cells that can be utilized in medical treatments, and that offer a number of very exciting potential opportunities – not only with coronavirus but in many other diseases as well.

What exactly is coronavirus?
Coronavirus is a respiratory virus, but this particular strain – which became a front-page news a few months ago – seems to have originated in China and is particularly virulent. Coronaviruses themselves are not new; in fact, the common cold is often caused by a particular type of coronavirus, but this one in its singularity is particularly devastating.

How serious is contracting the virus for the patient?
We're learning more as the pandemic goes on, but what is becoming clear is that for the very large majority of people infected with the virus, the symptoms are relatively benign – similar to a cold or influenza flu-like symptoms: fever, body aches, runny nose, sneezing and a cough. I have nine acquaintances at the moment who have been diagnosed with coronavirus. It just felt like a little bit of fatigue, a little bit of a cold, and suddenly they've been diagnosed as positive.

But it's the more seriously impacted patients that we're most concerned about. These are typically the elderly and those who have underlying health issues. These patients seem to be very severely affected and are causing the most concern, partly because of the impact upon the healthcare system, but also, ultimately, the fatality rate. As is often the case with pandemics, it is those who are elderly or infirm in some way that seem to suffer the most.

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What are the consequences of contracting the virus for the elderly or infirm from a health perspective?
Because it's a respiratory virus, it manifests itself in the lung and the upper respiratory tract. That means that when we see issues in these patients, it is often that they have progressed to more serious lung conditions such as pneumonia. They can then develop a further problem associated with the lungs called acute respiratory distress syndrome (ARDS). ARDS is when the lungs cease to work effectively as an oxygen exchange mechanism within the body, and that can lead to sepsis and organ shutdown.

Interestingly, the more serious manifestation of pneumonia, which leads to ARDS, is not uncommon, and not necessarily associated with coronavirus. ARDS has become front-page news because of coronavirus, but many patients in intensive care wards, pre-coronavirus, were there because they have ARDS arising from entirely different infections.

What is the standard course of care for somebody who presents with an infection leading to acute respiratory distress syndrome?
Unfortunately, the care is mostly supportive, largely because there are no antiviral drugs that are effective yet against coronavirus. It's managing the fever and the lung involvement, which, in the worst cases, involves complications that result in the patient going on a ventilator to assist their breathing.

Where would a new cell therapy come into treating ARDS?
At the point of considering a new cell therapy, the biology of ARDS and complications arising from pneumonia becomes very important.

We rely on our immune systems to keep us intact and healthy. Our immune system is constantly assessing the threats we encounter and defusing them, imperceptibly most of the time.

Unfortunately, what seems to occur in a proportion of patients is an overreaction of the immune system. That overreaction results in numerous problems that the body has great difficulty in overcoming, predominantly in the lungs. 

Sepsis is the same issue, where the body's overreacting to the infectious process. Sepsis is a major cause of mortality in intensive care wards around the world, and The Lancet recently published an accounting of the cost of sepsis, which made front-page news because it is so enormous. Everybody seemed quite surprised about it but all the intensive care staff just said, 'that’s what we've been telling you about for years.' 

The immune response should be like a laser-guided missile, which is very precise and can take out the target effectively, without destroying too much around it. Compare that to our patients who, relatively, have a nuclear warhead that not only takes out the target but everything within a 100 mile radius, resulting in organ failure and the patient's death. What we're trying to do with cell therapies is to try and bring that under control, helping the patient through the crisis so that their immune system can eradicate the virus without long-term consequences.

What are some of the issues in trying to deliver a cell therapy to patients at the minute?
Well, ‘at the minute’ is probably the key term, because everything is changing by the minute. The standard process, if one wanted to do a clinical study in patients with coronavirus infection using MSCs, is that you'd submit that to the regulatory agencies in the relevant geography – the US FDA (MD, USA), the MHRA (London, UK), or the TGA (Canberra, Australia). That trial would be reviewed and, if thought appropriate, approved to go ahead. That takes time and lots of money but is the normal process.

However, the situation right now is extraordinary, and that's leading to changes almost as we speak. I suspect that regulatory agencies around the world will start to think, what do we have to do? What can we do to support patients other than putting them on ventilators? 

Intensive care wards and general hospitals have a small number of ventilators, and there may be more demand for those ventilators than can be met by existing hospital resources. I don't know of any imminent changes, but it's entirely possible, that extraordinary measures will be taken to bring new therapies into the treatment paradigm for severely affected patients. 

We're still a ways away from an effective antiviral or effective vaccine. What we can do with these patients immediately, and where the need is growing, is to support them and to help them recover. That's potentially where MSCs may be useful. The findings out of China last week have triggered a growing interest in MSCs as a potential supportive therapy for patients with severe complications of coronavirus infection.

What are some MSC features that make them ideal for this sort of therapy?
To use an analogy, they’re the Fat Controller of the railway network. They exert a profound immunomodulatory effect on the immune system to ensure that it does not overreact and to ensure that its reaction is measured and focused, so much so that they have also been termed ‘medicine secreting cells’.

They signal the effector cells of the immune system and cause them to adapt to the circumstances. That means that rather than just wholescale destruction, which is what causes the problems in these patients, it's a more measured approach to allow the immune system to eradicate the infectious agent, the virus.

How do you envision the treatment looking, if the regulators allowed more experimentation and freedom in these times?
The treatment would most likely be administered through an IV infusion. That's the typical delivery modality for this type of systemic infection. There are other means of delivering the drug, but we're talking about a centralized disease, which means IV is probably the best way. Of course, these treatments would be in patients that are typically in hospital, if not in an intensive care ward, so an IV is already being used. That would mean you could just plug in the bag of cells, which is very easy.

From allogeneic sources like Cynata?  
That's right. Although it doesn't need to be, but you have to bear in mind that these patients are very sick. It's highly unlikely that an autologous source is going to be appropriate. An allogeneic product, or an 'off-the-shelf' product, is going to be the most appropriate here because you just don't have the time to suck MSCs out of the patient's bone marrow or adipose tissue, purify them, and do all the steps necessary. In any case, donating their own tissue for this purpose is the last thing you probably want to put them through.

Is there anything further you'd like to discuss?
I think the important point to make is that, in this era of uncertainty, a product that is safe – and MSCs appear to be very safe – and that appears to have a good biological basis to work may soon have regulators around the world paying it a lot more attention, especially as the need grows. 

Of course, we all hope it doesn't escalate, but the situation in Italy is dire with some difficult triage decisions being made by healthcare professionals: who's going to get on a ventilator, who are we going to treat and who are we going to support, versus who's going to sit out there in the car park not being treated. 

I hope this is not necessary, but I think we'll see an increasing level of attention on experimental therapies that have a rational basis, which, thus far, have proven to be very safe. Although we clearly don't want to be testing things if we don't have any knowledge about the safety, most of the clinical studies that have been conducted to date with MSCs have shown a clean safety profile, including our clinical study. I think that gives health regulators some confidence that absent anything else to offer these patients, we should give it a crack.  

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