The life of a T cell isn't glamorous. Its job is to protect the body from illness, meaning frequent battles with foreign bacteria or viruses. Cancer is another foe, but a cache of tools allows tumor cells to hide from and weaken the immune system.
With this in mind, drugmakers have found promise in reconfiguring patients' immune systems to better fight cancer. As of early December, the Food and Drug Administration had approved 26 treatments that do just that. Two of them are part of an emerging therapeutic class called chimeric antigen receptor (CAR) T cell therapy.
Unlike many other immuno-oncology drugs, CAR-T therapies present unique supply chain challenges. Their production begins with the extraction of T cells from a cancer patient. The cells are shipped to a manufacturing facility, where they're genetically engineered to more effectively target tumors before being sent back for infusion.
Along the way, the cells must be kept extremely cold, or else they could die. The cancer patients, who typically have failed other forms of treatment, could also die if the process doesn't happen fast enough, or if they're given someone else's cells.
Links in the pharmaceutical supply chain got better at dealing with those intricacies as CAR-T therapies evolved from a novel idea to a realized market. New software platforms now provide drug companies with more comprehensive data on who handled the therapy last or what stage it's at within the supply chain. And advancements in cold storage, containers and technology integration have made shipping the therapies more viable.
The CAR-T market is still in its infancy, however, and there's a general agreement among stakeholders that the supply chain forming around it has room to grow.
Chain of custody, chain of identity
Pharmaceuticals meet many pairs of hands as they go from production facilities to hospitals and pharmacies.
Collectively, those hands form the chain of custody, which is especially important for personalized therapies, such as CAR-T, that need to move through the supply chain at a rapid clip. Gilead Sciences Inc., for instance, says it turns around a dose of Yescarta (axicabtagene ciloleucel) in about 17 days from apheresis to reinfusion into the patient. Knowing who was last in contact with a package of cells, whether it be a carrier, an engineer or a healthcare provider, enables manufacturers to see where it is on the route and where to look if something goes awry.
Technology that can provide that type of information — which is routinely siloed among the chain's various stakeholders — has therefore become a necessity, giving rise to companies like Vineti Inc. and Cryoport Inc. that, through their platforms, can integrate IT systems, track shipments and keep logs of a product's temperature.
And given the potential health risks, personalized therapies also require a full-proof chain of identity that makes clear the specific patient who is to receive the therapy.
Without appropriate software, "it's swivel-chair monitoring from one system to the next, and that chain of identity and chain of custody is very easily compromised," said Amy DuRoss, CEO of Vineti. "It's an impossible task without a level of sophistication that affords the transparency and control that a software solution ... provides."
Some argue, however, that the CAR-T chain of identity hasn't seen as much innovation as other parts of the supply chain, continuing to use traditional identifiers such as birth dates, patient initials and unique barcodes.
"Chain of identity still has room for improvement," said Knut Niss, chief technology officer at clinical-stage CAR-T drugmaker Mustang Bio Inc.
From A to B, then back
It's in the treatment setting where these pieces of the CAR-T supply chain appear most unsettled.
Each hospital or treatment center operates differently; there's no FDA guideline for who should pack the cells for initial shipment or the number of clinical investigators who should handle them upon return for infusion.
"Some hospitals may require that the product gets to the hospital before they even start the lymphodepletion, which really means now the product has to be stored at the hospital under the right conditions for an extended period of time," Niss said.
"Other hospitals might be fine saying we start the depletion without the product in our hands, which is of course a risk because if something happened to the shipment, there's no product to be infused."
The variability underscores just how differently each piece of the CAR-T supply chain operates. Production facilities, in contrast to treatment centers, are bound by strict Good Manufacturing Practice (GMP) requirements. If federal regulators find the facility to be non-compliant, they could stop treatments produced there from coming to market.
"It just brings this whole different level of complexity because the process is the product, you're not simply spitting out pills from a single protocol, mass-produced at a single facility, and shipping them out on pallets," DuRoss said.
Manufacturing a CAR-T therapy
A healthcare provider connects the patient to an apheresis machine, which draws in blood and separates out one of its components: either plasma, platelets, red blood cells or white blood cells. In the case of CAR-T, it's T cells, a type of white blood cell, that matter.
2. Transport to manufacturing site
The T cells then go off for testing. If they pass, they're shipped out to the manufacturing facility. Given the quick turnarounds needed for CAR-T therapies to work, they're normally sent via airplane, with trucks ushering them to and from the airport. All the while, the cells must be kept at a frosty -150°C.
At the manufacturing plant, engineers use viral vectors to insert new DNA into the T cells. That DNA gives rise to synthetic receptors on the surfaces of the T cells, in turn allowing them to attach to proteins located on tumor cells. Engineers then test the quality of the rejiggered T cells and work to multiply them by the millions.
4. Return trip to hospital
The new cells are then repackaged and make the return trip to the patient's hospital or treatment center. Carriers again must ensure the cells stay incredibly cold and get to the final destination as quickly as possible. Gilead and Novartis are aiming to do the entire process in 17 and 22 days, respectively.
5. Administration to patient
At the treatment facility, patients undergo lymphodepletion and are infused with the finished therapy. Perfecting the timing and preparation for last step has proven to be one of the biggest concerns among members of the CAR-T supply chain.
To be sure, the manufacturing and transportation processes involved with CAR-T remain quite complex. But they've also solidified as the global pipeline for CAR-T and other cell and gene therapies filled out. United Parcel Service Inc. offers one such example: its acquisition of Marken Ltd. in late 2016 gave the shipping giant a suite of life sciences-focused supply chain solutions, as well as access to nearly 50,000 clinical trial sites.
"Five years ago I would have said 'yeah, shipping is the problem,' because the FedExs, the UPSes of the world, they don't really deal much with cell therapy. Fortunately now, we're in the situation where some of the shipping companies, if not all, have developed specific systems and mechanisms for cell therapy products," Niss said.
Already, shippers are looking beyond the global position systems and packaging technologies that fostered the CAR-T supply chain.
Ariette Van Strien, chief commercial officer at Marken, noted in an interview that her company is trying to dive deeper into automatization. "That's the key driver in any case," she said, "try to reduce the manual intervention as much as possible in order to have a way that you can control the solution remotely and intervene as well," when needed.
As the CAR-T market saturates beyond Gilead's Yescarta and Novartis AG's Kymriah (tisagenlecleucel), the supply chain supporting it will surely feel the pressure to scale up. Each member faces different growing pains.
At the manufacturing plants, there's interest in devising tests that would analyze how well the manufacturing processes are working before the cell product is churned out.
"Because the process is so long and complicated, you don't want to get to the end and find out there's a problem with the batch," said Mark Stevenson, chief operating officer at Thermo Fisher Scientific Inc. "One of the areas we're focusing on is what technologies can we apply ... to look at attributes in the manufacturing that we could use as control points rather than functional testing at the end."
Shippers, meanwhile, are preparing for cell therapies to branch outside of cancer and into new therapeutic areas. A report from research firm CBR Pharma Insights published in February counted 985 in vivo gene therapies in the global drug pipeline, as well as another 354 CAR-T therapies under investigation. In addition to oncology, the report found central nervous system disorders, genetic and ophthalmic disorders as key targets of the gene therapy pipeline.
"Where we're looking at is what are the different indications. CAR-T is the one which is, right now, very interesting but it's only one of the ways to develop these personalized therapies," Van Strien said.