Life transport

Mention the cold chain today and you’ll probably conjure up images of just-in-time deliveries made using the latest refrigeration systems. But go back a few centuries and the cold chain was far slimier – and smellier. Eager to bring their catches to distant inland markets, UK fishermen began transporting their fish in ice way back in 1797. From these windswept beginnings, of course, the cold chain has exploded. By the 1930s, refrigerated train cars were carrying chilled foods vast distances. By the 1950s, new post-war highways had moved the cold chain to the open road.

Our modes of transport haven’t changed much since then, but the next set of advances can be discerned in the statistics, if nowhere else. According to the IMARC Group, the global cold chain industry in healthcare alone was worth almost $11.5bn in 2018, a figure expected to rise to nearly $17bn by 2026. With economies like China and India clambering to the top of the global pile, and the FDA approving dozens of heat-sensitive pharmaceuticals each year, these enormous figures aren’t necessarily surprising. Yet with innovations come challenges – especially in the realm of cell and gene therapy (CGT).

Able to replace faulty genes, or using cells to carry medicine through the body, CGT could quickly overturn our concept of what’s medically possible – but only if we figure out the cold chain first. That’s far from easy. With CGTs even more delicate than regular treatments, an imperfect supply chain risks destroying the cargo long before it actually helps patients. Not that the situation is hopeless, though. By exploiting the newest technology and philosophies that the cold chain can offer, scientists and pharmaceutical companies may soon bring CGT to many more patients – and even develop new therapies far closer to the people that need them.

Dr Sanjay Srivastava, the CGT lead at Accenture, understands the power of CGT better than most. With a long career in management consultancy behind him, he’s been working in biopharma for years, helping companies understand and exploit the colossal power of CGTs. And, as Srivastava makes clear, this is less a matter of fixing one illness or another; rather, CGT has the potential to work across medical life. “The ongoing research suggests that they could be used for treating or curing a wide range of diseases,” he says – everything from cancer and cystic fibrosis to heart disease and diabetes.

Genie out of the bottle

So how do these seemingly miraculous treatments actually work? Gene therapy is fundamentally quite simple: doctors introduce genetic material into cells to compensate for abnormalities or create beneficial proteins. Cell therapy works similarly, with physicians transferring healthy cells into a patient to cure disease, or else to spread medicine around the body.

Certain types of cell therapy, explains Tamas Masztis, senior director of the cell therapy supply chain at Kite Pharma, can actually induce antibody cells to recognise and attack unwanted interlopers. “This enables your body to fight cancer cells by itself,” he explains. Little wonder, then, that CGT is becoming such big business. Though it accounts for just 1% of the value of the global pharmaceutical industry, it is being used in over 1,000 specialised clinics worldwide, and the FDA predicts that it will approve up to 20 CGT products a year by the middle of the decade.

As that 1% figure implies, though, manufacturers and researchers have not had everything their own way. The cold chain in particular has been a major obstacle. That can be understood partly with reference to CGT itself. Because CGTs are so sensitive to temperature changes – let them get too warm and cell numbers will quickly drop, with some cells needing to be as cold as −150°C – they need to be carefully monitored en route. Add to that the vital importance of the “shock and orientation” of a sample, Srivastava explains, and traditional shippers quickly start to struggle. “Today, there are very few couriers with the capabilities to meet the rigorous quality standards, [and] special handling and tracking requirements for shipments under refrigerated, frozen and cryogenic conditions.”

It hardly helps that the CGT supply chain is vastly more complex than that of conventional medications. When a patient goes to the hospital for a migraine or broken thumb, chances are their drugs have come directly from the factory. But if they’re receiving gene therapy for, say, cancer, in the US – where there are only 218 certified CGT institutions – the treatment will probably have meandered.

A patient’s new cells will certainly have visited a regular hospital, just like regular drugs, but they’ll probably have been shipped to a specialised CGT clinic too. Remember, after all, that CGT therapies typically come from patients themselves, their cells removed from the blood via a process called apheresis, before being taken away and returned to them later. So-called ‘allogeneic cells’ can be taken from donors but, either way, the cells have a lot of travelling to do. And with over 500 manufacturers to deal with globally, even the most efficient shippers can quickly be overwhelmed.

Total network solutions

Talk to any CGT expert worth the time and one word is likely to be on their lips: networks. A simple word, yet one that encompasses much of what could happen to the CGT cold chain of the future. For if networks have traditionally been a burden for the CGT cold chain, they might just be the best way for the industry to cope with demand going forward.

It works like this. Rather than having the network scattered between donors, hospitals, specialised clinics and patients, some enterprising companies are dragging them together into a single location, slackening the cold chain as they go. If anyone wanted to see what ‘network manufacturing’ means in practice, they couldn’t do much better than the Centre for Breakthrough Medicines, where property impresario Brian O’Neill is funding a $1.1bn gene and cell treatment manufacturing operation. It is gathering academics, healthcare leaders and scientists together in a repurposed GlaxoSmithKline laboratory in a small Pennsylvania town called King of Prussia. A few miles north, near Boston, experts from Harvard, MIT and industry are working on a similar project. All very grand – but, as Srivastava explains, it really is incredibly useful for fixing the cold chain too.

Rather than rushing vulnerable cells around on the backs of lorries, doctors can treat patients and harvest their cells in a single spot. “There is tremendous interest from both traditional and non-traditional players to catalyse the development of CGT therapies by shortening the path between research and clinical application,” he says. Masztis agrees, and notes that even before these new facilities open their doors, there is plenty that companies can do already. New technology is vital here, he says, explaining how automation can now get a treatment from the factory to the patient in just 48 hours. “All the pipettes and needles can go into one big machine and then it finishes the job by itself. This certainly brings costs down, and increases the reliability of the manufacturing process for the patient.”

All in one wheelhouse

Beyond that, both Srivastava and Masztis look forward to the arrival of so-called ‘hub and spoke’ connectors – next-generation logistics providers that facilitate everything from transferring cells to manufacturers, to delivering finished treatments to patients. Borrowing an airport analogy, Srivastava explains how these connectors will have ‘control towers’ that let them understand every facet of the supply chain, which will allow them to work closely with doctors, patients and manufacturers. Masztis is similarly optimistic, describing how these hub-and-spoke companies are “potentially the future” of how the CGT cold chain is run.

‘Potentially’ is probably an important word to bear in mind. These unified facilities and efficient suppliers all sound fantastic, but organising them in practice is a different story. A particular challenge, Masztis says, involves securing the supply chain for autologous therapies – or ones built from the cells of individuals themselves. That means establishing a chain of identity, he explains, ensuring a patient gets the right cells back after they return from the lab or factory.

None of this is simple – indeed, maintaining the resources needed to keep an eye on individual cells across many miles will probably always be a challenge. This is especially true when you factor in national borders and the variations in regulatory requirements they demarcate.

All the same, you get the sense that its revolutionary potential is just too huge for these problems to keep CGT at bay for long. For his part, Masztis imagines a world where one healthy donor could help treat the illnesses of dozens or hundreds of people, something his team at Kite is already working on. “We want to stay ahead of the competition, stay in the lead.” And no wonder. With all that CGT is already doing, and has the potential to do, it makes sense to keep ahead – if only the fishermen of Georgian England could come back and see what they began. Did anyone keep them on ice?

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Cell therapies for Covid-19

One of the most dangerous complications for patients with Covid-19 is acute respiratory distress syndrome (ARDS). Even before the pandemic, the condition affected 500,000 people a year across Europe, the US and Japan, but that didn’t mean anyone was prepared for what was coming. The surge in ARDS cases caused by the virus stretched supplies of ventilators to their absolute limit, and even patients treated with the devices died at terrifyingly high rates.

Thankfully, since the outbreak first reached Europe and the US, physicians’ understanding of Covid-19-associated ARDS, and their ventilatory strategies for treating it, have improved markedly, helping to contribute to a considerable drop in mortality rates. Still, with many survivors struggling to breathe months after they fought off the infection, the pandemic has exposed just how destructive and heterogeneous ARDS can be.

In doing so, however, it has also helped to focus the attention of CGT experts on developing the first specific treatments for ARDS. US-based cell therapy biotech Athersys has already reported results from a phase-I/II study showing that treatment with stem cells derived from bone marrow donations reduced mortality from 40% to 25% in patients with moderate to severe ARDS. It is now working to scale up manufacturing as it moves into the next trial phase.

Similarly, Israeli biotech Pluristem Therapeutics, which uses immunomodulatory placenta-derived stromal cells, has used its technology to treat numerous patients as part of a compassionate use programme, and is currently moving into phase- II trials. In total, the Alliance for Regenerative Medicine is currently tracking 11 ongoing clinical trials, and an additional 24 preclinical studies for cell therapies against Covid-19.