After years of intensive research and development, cell therapies are finally having their moment. In the past year, the FDA has approved two CAR-T cell (chimeric antigen receptor T-cell) therapies, with stem cell treatments in hot pursuit as they enter late-stage clinical trials. While regulatory body recognition is an important milestone for the field, great challenges in the long-term sustainability of the industry remain. By proving that cell therapy can be effective, researchers have won an early battle – but to win the war they must ensure that this therapy is effective and accessible for the tens of thousands of recipients in the years to come. Delivering these therapies at this scale in a reliable and affordable manner will require a paradigm shift in not only manufacturing but the subsequent supply chain and patient care that follow.
Unlike proteins and small molecule drugs, cells are living entities derived from living donors. Once harvested from the patient, they continue to be influenced by environmental and temporal changes during the manufacturing process. When generating large batches of cells, this responsiveness leads to variability that can result in major batch-to-batch differences in product quality. Even with careful handling, this variation can increase phenotypic variability and more importantly, hinder their therapeutic potency. The variability in large-scale manufacturing has been especially challenging in the expansion of mesenchymal stem cells (MSC’s). Some researchers believe that it is this variability which is responsible for the ongoing difficulties in achieving statistically significant efficacy in human trials.
With the founding of institutions like Canada’s Centre for Commercialization of Regenerative Medicine (CCRM), STEMCELL Technologies recently announced $138 million cell manufacturing facility in Burnaby, B.C, and biotech companies like Mesoblast, RoosterBio, and Excellthera, there is major work being done to address the manufacturing problem. The success of cellular scale-up is assessed through three major critical quality attributes (CQA): identity, purity, and potency. Identity and purity are relatively easy to assess in the lab, but reliably determining the potency of a dynamic, living therapeutic is still not quite where it needs to be. Dr. Peter Zandstra, Chief Scientific Officer for the CCRM and Chief Technical Officer of Excellthera explains: “Many of the markers to assess cell therapies right now are surrogate markers, meaning they don’t directly measure the therapeutic function of the cell but instead, correlate to it.” Zandstra emphasizes that this is especially a problem in clinical translation as at the laboratory stage, “we’re still one step away from biology that were looking for in the patient”.
The potency problem can also vary widely not only from batch-to-batch but also patient-to-patient, as often cell therapies are reprogramming the patient’s existing immune system to elicit a therapeutic effect. In predicting potency for different patient populations, Phil Vanek, General Manager Cell Therapy Strategy in GE Healthcare, suggests translating big data analytics into predictive models may ultimately be the answer: “We need the collection of large biological data sets that track the appropriate inputs and outputs of the therapy…we can then mine that data to better predict what the outcome will be with certain process and patient inputs”.
In fortifying the cell therapy industry, there is also an incentive to streamline the supply chain responsible for transporting the cells before and after expansion. These processes diverge according to the two major streams in cellular manufacturing: scale-out and scale-up. Zandstra explains: “For patient-specific therapies like most current CAR-T’s then you’re trying to scale out the process and make it robust and repetitive. In MSCs you have a bulk product that can treat many thousands of patients with one donor – that’s’ a scale-up”. While scaled up cells can be shipped in a similar manner to cell lines used in basic research, the supply chain is much more complex for scaled-out therapies as the cells must be transported – quite literally – from vein to vein in a timely manner. The supply chain for cell therapies involves health systems, hospitals, developers, manufacturers, as well as traditional logistics providers and distributors. Vanek notes, “one of the reasons why these cell therapies are so expensive is because the elements of the supply chain process are all disconnected today… from a supplier perspective, it’s very inefficient and inefficiency is driving up cost”.
Companies like Gilead subsidiary, Kite Pharma are hoping to break down supply chain silos by controlling the entire vein-to-vein process. Through their Kite Connect service, all aspects of the supply chain will all be overseen by one company to help reduce redundancies and alleviate inefficiencies. In another approach, Asymptote – a subsidiary of GE Healthcare – is working to improve the ‘cold-chain’ technology which cryopreserves the cells for the entire transportation process in an endeavour to provide a little more flexibility in the supply chain timeline.
In another effort to simplify the supply chain process, scientists are hoping to transform scale-out strategies into a more flexible scale-up process. Currently, scaled-out therapies like CAR-T cells rely on a single donor that ‘matches’ the immune profile of the recipient. To circumvent the matching process, most scaled-out therapies are autologous, meaning the patient themselves serves as the donor. To shift toward a scaled-up version of CAR-T cells, a single donation must be able to make bulk quantities of cells for multiple patients. The donated cells, however, must be universally match the immune profiles of all recipients. This endeavour is being hotly pursued by the aptly named Universal Cells, a biotech company based in Seattle that uses gene editing to ‘scrub’ stem cells from immune recognition. Zandstra adds this could also improve issues related to variability in patient-specific cells: “You get cells from young and old patients and individuals in different stages of the disease process which generates a lot of variability. If you can move to a more universal donor source of cells and then do your large batch scale-up, you can reduce a lot of that batch-to-batch variability”.
Automation is another strategy that is hard to ignore when searching for ways to improve cellular manufacturing. Cleanrooms and laboratory technicians are still the workhorses of the field, but with yearly operational costs that often exceed US$400,000, this aspect of the manufacturing process is viewed by some as the most pressing obstacle in sustainable and economical cell therapy production. In response, Biospherix Ltd. has developed a ‘cytocentric approach’ which replaces cleanrooms and technicians with a ‘hands-off’ automated system for cell culture. Vanek is quick to point out, however, that there is still some work to be done before automation can be fully implemented: “Automation is what you do when you’ve locked down a process to reduce variability…[currently] you have patients entering a manufacturing process with different genetic, environmental and treatment backgrounds – simply stated: we need to understand a lot more about the biology to determine the predictability of a process. Once we get that then automation shouldn’t be a problem”
Beyond the cell product, the delivery and aftercare of patients following treatment is also a major consideration in longevity. The complex nature of this treatment has for the most part, limited cell therapies to areas with the facilities to assess and monitor cell therapy recipients. In addition to the obvious impact this has on accessibility, added cost to the healthcare system is also a significant obstacle.
Dr. Michael Rudnicki, Director of the Stem Cell Network in Ottawa, Canada suggests that health economists may have a major role in properly assessing the issue for the long-term. “We need to evaluate the cost to our society of supporting someone with a disease, versus the cost of delivering health care”. Rudnicki adds: “The government looks at the silo of the healthcare system. What they don’t look at is that someone with a [life threatening] disease has an economic impact: being taken out of the workforce, not paying taxes, and [consequently] their kids may not get an education”. Freeing individuals from debilitating diseases and treatments goes far beyond saving a life; these advances have the potential for a major societal and economic impact that may, in fact, overcome the steep costs upfront. Even so, there are high hopes that the costs of cell therapies will also improve with time. Vanek surmises “With the efficiency of supply chain, reproducibility, competition from multiple vendors – all those economic elements will come together [to decrease cost]”.
Though complex, cell therapies have the potential to define a new pillar in modern medicine. Scalable solutions for the outstanding issues related to the manufacture, delivery, and accessibility of cell therapies, however, is paramount for a therapy that ‘sticks’. For those tasked with ensuring their continued success and mass adoption in modern healthcare, the work has just begun.
Erika Siren is a Ph.D Candidate in Biomaterials Chemistry at the
University of British Columbias‘ Centre for Blood Research. She is based
out of Vancouver, British Columbia.