Previously in this series, we've discussed how the Terumo Research Institute (TRI) contributes to growing industry knowledge. For one, the institute conducts clinical studies, as well as supporting investigator-initiated studies. Members of the TRI team have now published exciting study results, including the unexpected dominance of stem-like memory T cells (Tscms) — known for their promise in treating blood cancers — resulting from an automated cell expansion process. Their peer-reviewed article appeared in Cytotherapy, a leading industry publication of the International Society for Cell and Gene Therapy (ISCT).
Early Goal: Study Effectiveness of Needle-to-Needle Modular Automation
This team – Annie W. Cunningham, Mark Jones, Nathan Frank, Dalip Sethi, and Mindy M. Miller – set out to evaluate the quality and yield of a cell therapy product manufactured using a modular "needle-to-needle" automation platform. They began with the Spectra Optia® Apheresis System, an industry-leading apheresis and cell collections platform, to collect targeted donor cells, which were then expanded with the Quantum Cell Expansion System. After expansion, the team used the Finia® Fill and Finish System to automate final formulation, aliquot the product into bags, remove air, and seal the product bags, before continuing to cryopreservation. It was the first time this continuum of devices from Terumo Blood and Cell Technologies was used in a published study.
The full sequence using these systems demonstrates an end-to-end process that customers could adapt for their own unique manufacturing needs. "Modularity in automation of these processes is poised to become the gold standard," according to Dalip Sethi, PhD, Director, Scientific Affairs CTT/Innovation. "Instead of taking place all on one device, our automation approach is highly integrated, but modular. You have the freedom to change just one part of the process, and you free up capacity on each device as you move to the next step. We also have the expertise and insight to help the customer optimize each step."
An Unexpected Finding in Cell Phenotype
Based on their experience with this integrated platform, the team fully expected to achieve high yield and maintain T-cell phenotype and functionality — and they did. Surprisingly, they also observed that cell types evolved during the manufacturing process. After the cells were cryopreserved, thawed, and rested for 24 hours — mimicking what would occur in the human body during the first 24 hours after infusion — they found that stem-like memory T cells (Tscms) were the dominant cell phenotype. That was a marked difference from the cell population profile before expansion, and an intriguing result, because these sought-after cells have unique potential.
The Importance of Tscms
Mindy Miller, PhD, an Immunologist and Lead Research Scientist, explains that memory cells "remember" previous antigens to which they have been exposed, which allows them to be activated more quickly when they encounter the same antigen again. Stem-like memory T cells, because they are stem cells as well as memory cells, provide not only long-lasting immunity (because they are developmentally young cells) but also diverse immunity, because they can generate multiple types of T cells when they're transferred back into the patient's body. Because of their ability to differentiate into many different cell types, Tscms excel in the immunological fight.
According to Annie Cunningham, Field Application Scientist, "These stem cell memory-like cells have been shown in the literature to potentially have more curative abilities in cell therapy for hematological cancers. That's why this particular set of cells is so important. In the field, scientists are trying to figure out how to generate them, using very expensive reagents and genetic modifications. And we were able to generate them automatically on Quantum. This is another way that automation helps drives down manufacturing costs to make therapies more accessible for more patients."
What's more, the Tscms in this study exhibited little evidence of exhaustion. As Miller explains, "There are innate mechanisms that tell T cells to 'turn off.' When a T cell is activated, these are upregulated at the same time. It's a fine balance between having a T cell that is healthy and activated, but not so activated that it becomes exhausted and stops working."
Perfusion May Be the Key
The team's hypothesis is that this change in phenotype is related to the modular automation process they followed, particularly the expansion phase. Quantum's hollow-fiber perfusion technology allows continuous flow of nutrients and oxygen into, and waste out of, the expanding cells, much as these processes happen in the human body. Without further testing, though, they can't be sure this is the reason for the phenotype results. It's also important to note that this study used cells collected from healthy donors; in a clinical scenario, a patient's own cells are collected to create a cell therapy product that is then returned to that patient.
What's Next?
The TRI plans to compare the performance of this integrated automation platform with that of other devices. In addition, they want to continue testing different manipulations of donor cells on Quantum, such as different feeding strategies, to see if there is any effect on the development of Tscms. This would help solidify the hypothesis that hollow-fiber perfusion helps to generate these cells.