by Yelena Bronevetsky, PhD, Director of Product Management, Xcell Biosciences.
Cell therapies hold incredible promise for treating diseases that have long been considered incurable — but they also face a litany of challenges that must be addressed before these treatments can become more broadly used in mainstream medicine. Cell therapies are too expensive; costs must come down to expand access. They take too long to produce, with some vein-to-vein timelines so long that physicians won’t prescribe them for patients because they know their health is likely to decline to the point of ineligibility by the time the therapy is ready. These therapies can also vary substantially in their effectiveness, with unreliable potency and persistence of therapeutic cell populations.
Those are just some of the challenges in cell therapy development and delivery today. Collectively, these problems have resulted in slower uptake than expected for these transformative treatments. In 2019, MIT scientists published a carefully reasoned prediction that cell and gene therapies would be used to treat about 350,000 patients by the year 2030.1 As of 2024, the largest category of these therapies, CAR T cell immunotherapies, had been used for just 34,000 patients globally.2 Meanwhile, at least 100 cell and gene therapies have been approved worldwide, and there are thousands of candidates in development.3
There is ongoing debate about whether the slow adoption of cell therapies is due more to limited demand or to limited supply. Either way, though, many of the challenges facing these therapies can be addressed through improved manufacturing processes. Better, more reliable approaches can reduce development costs, shrink manufacturing timelines, and improve potency and persistence.
However, there is a major problem in cell therapy manufacturing today. It stems from a disjointed approach: methods are developed and honed in small-scale R&D platforms, and then transferred to entirely different, large-scale manufacturing platforms. There is nothing seamless about this transition. The use of different technologies thwarts efforts to achieve consistency and reproducibility, and it means that an entirely new optimization effort must be undertaken once the R&D methods are transferred to manufacturing. A better approach would involve using the same underlying technology across the spectrum to ensure that the cell therapies delivered to patients match the ones developed in the R&D phase.
Disappointing outcomes
The disconnect between R&D and manufacturing methods for cell therapies may help to explain why so many high-performing therapeutic candidates fail when they reach actual patients. For example, scientists at City of Hope in California evaluated a CAR T cell therapy candidate for prostate cancer.4 In preclinical studies using xenografts, the candidate elicited robust antitumor effects, particularly with the incorporation of a costimulatory domain that boosted persistence. When this therapy moved into a phase 1 trial, though, the team observed limited persistence after four weeks and only modest improvements in tumor size.5
Similar reports came from scientists in Korea working on a CAR T cell therapy for the highly aggressive pancreatic ductal adenocarcinoma.6 They reported strong preclinical data with a mouse model, including complete remission in several mice. But when the therapy moved into a small phase 1 trial at the University of Pennsylvania, it showed limited clinical efficacy.7
Improving incubators
While the disappointing outcomes of these two therapies — and many other candidates — cannot be blamed entirely on manufacturing issues, it is reasonable to conclude that better process consistency across the preclinical-to-clinical spectrum would lead to more predictable outcomes for cell therapy candidates as they move from animal models to human trials and, eventually, to approved clinical use.
For cell therapies, all of these processes — from small-scale research protocols to high-throughput manufacturing methods — rely on incubator platforms. The cell incubators that have been laboratory workhorses for decades are being used to grow today’s cell therapies, but it is likely that these advanced treatments will require a more sophisticated incubation technology. For optimal results, the environmental conditions used within these systems should match as closely as possible the biological microenvironment in which these edited or enriched cells are expected to carry out their therapeutic duties.
In particular, conventional cell incubators lack adjustability for two settings that are essential for mimicking biological microenvironments: oxygen and pressure levels. These levels vary quite a bit throughout the body; tumor microenvironments tend to have extremely low oxygen levels and high pressure levels. In order to expand cells under similar conditions, scientists must be able to carefully tune oxygen and pressure levels in the incubator. Growing therapeutic cells under conditions that are not physiologically relevant leaves them unprepared for the harsh environments they will encounter in the body.
Indeed, studies of cell therapies expanded in newer incubators that allow users to adjust oxygen and pressure levels to match target tumor microenvironments show increased potency, persistence, and tumor-killing activity compared to the same therapies grown in conventional incubator conditions.8-10 Preparing cells for the environments they will face in vivo appears to be a more effective strategy — and one that can be used just as easily for R&D stages as for clinical manufacturing since these more sophisticated incubator platforms are available with scalable throughput.
Impact on manufacturing
This relatively small change — shifting to an incubation platform where oxygen and pressure levels are tunable — has significant implications for many of the challenges facing cell therapies. Most obviously, it creates cells with higher potency and persistence, increasing the chances that a cell therapy will trigger the desired effect in vivo. This improvement could help make cell therapies effective for more people, addressing the problem that these treatments are effective for just a fraction of patients today.
With improved potency and persistence, it could also be possible to reduce the number of cells required for a therapeutic dose by an order of magnitude or more. Today’s therapies can call for billions of cells, which is why manufacturing timelines are so long. If an effective dose could be delivered with tens of millions or perhaps millions of cells instead, that would dramatically shorten manufacturing workflows and reduce vein-to-vein timelines. Meanwhile, smaller doses created in less time would reduce manufacturing costs, potentially allowing biopharma companies to address the high costs of cell therapies.
Despite their success for bench research in the past, conventional incubator platforms are contributing to the challenges facing cell therapy development today. A new generation of incubator technology incorporates tunable oxygen and pressure levels for more physiologically relevant results, and some of these platforms are available for both small-scale process development and for large-scale manufacturing to enable easy protocol transfers from one stage to the next. A new approach to incubation technology could help usher in the next leap forward in cell therapy development.
About the author
Yelena Bronevetsky, PhD, is Director of Product Management at Xcell Biosciences. Yelena completed her PhD and postdoctoral training at UCSF, specializing in T cell immunology. She began her career at Berkeley Lights, where she developed single cell T cell assays before transitioning into product management and marketing roles at Berkeley Lights and Accellix. She now leads product initiatives at Xcell Biosciences, advancing next-generation cell therapy manufacturing platforms.
References
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3. American Society of Gene & Cell Therapy (ASGCT) and Citeline. Gene, Cell, + RNA Therapy Landscape Report: Q1 2024 Quarterly Data Report. April 11, 2024. https://www.citeline.com/en/resources/asgct-q1-2024-report
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