Shortening the time allotted to cell expansion in CAR T-cell therapy production could yield more effective, lower-dose products that get to patients sooner than those made using current methods.
The steps involved in making a CAR T-cell therapy—separation, enrichment, activation, modification, expansion, harvest, and cryopreservation—do not actually take a long time—usually between 10 and 21 days.
Yet, for the seriously ill patients who need them, the wait can still be too long. Analysis in 2024 suggested that some 30% of therapies made each year go unused, because the intended recipient’s health deteriorates while the product is being made.
As a result, reducing “vein-to-vein time”—the time required to turn patient-derived material into a therapy and administer it—has become a goal for the CAR T industry, with most efforts focusing on process efficiency or decentralized production.
Contracting expansion
Another way of reducing vein-to-vein times would be to shorten ex vivo expansion, according to Marta Costa, PhD, and colleagues at Portugal’s iBET, who say a “rapid manufacturing” approach would yield more effective, more consistent therapies.
“Rapid manufacturing changes the manufacturing goal as, instead of maximizing the number of cells produced outside the body, it aims to make fewer but fitter cells, by limiting expansion to three days or less.
“This preserves naïve and stem cell-like memory T cells, which proliferate and persist much better once infused, and this can, ultimately, result in lower CAR T cell doses,” she tells GEN.
Fitter cells
Under the current manufacturing paradigm, expansion processes run for as long as it takes the culture to achieve a desired density—often in the order of 10⁸ cells. The problem is that, after this period, the cells are often fully differentiated and exhausted.
Limiting expansion would increase the proportion of “fitter” naïve T cells harvested and, according to Costa and colleagues, produce therapies as effective as those made from fully differentiated cells, but at a much lower dose.
Achieving such precise control over shortened production processes will require innovative digital technologies, Costa says.
“Automation is what makes speed safe and allows for reproducibility. It also makes decentralized and point-of-care manufacturing realistic, allowing CAR T cell manufacturing to run at many hospitals supported by a closed, standardized and sensor-equipped system that is essential to ensure product quality.”
Costa cites the CliniMACS Prodigy and Lonza’s Cocoon as technologies that could facilitate the approach, adding, “They are being explored for rapid CAR T cell production as they integrate the steps from leukapheresis to final product in one closed system.
“Besides,” she continues, “to truly allow CAR T-cell therapies to rely on rapid manufacturing processes, faster analytics for product release are needed as several assays still take a week or more to assess product safety and potency.”
AI modeling also has a potential role to play, according to Costa.
“At the moment, most CAR T cell manufacturing processes follow a fixed recipe that is applied regardless of how patients’ cells respond. AI and data-driven approaches have the potential to shift this paradigm by predicting how cells will grow and differentiate, while enabling continuous, online monitoring of cell state.
“These insights can then be used to dynamically adjust process parameters and steer cells toward a desired quality phenotype. Ultimately, this could enable more adaptive manufacturing strategies, including selecting the optimal harvest timepoint based on the evolving state of the cells rather than a predefined culture duration,” she says.
“The evidence increasingly shows that cell quality matters more than cell quantity. Shorter processes produce fitter cells, cost less, increase capacity, and help patients who cannot wait weeks. That combination is hard to argue against, and it is also one of the reasons in vivo CAR T cell strategies, which remove ex vivo manufacturing altogether, are rapidly gaining momentum. We will see what the future holds.”