January 15, 2018 (Vol. 38, No. 2)
Christina Bennett Freelance Writer GEN
As Milestones Are Reached, Best Practices Will Become Less Hazy
Cell therapy is the delivery of living cells to treat, or potentially cure, a person’s disease. The transplantation of hematopoietic stem cells from a donor to a recipient to create bone marrow, for instance, is one well-established form of cell therapy.
The newer forms of cell therapy involve delivering other types of cells, such as T cells, to a patient.
One notable hurdle in cell therapy is being able to manufacture a consistent product on a large scale, which will increasingly become a concern as new cell therapies enter the clinic and subsequently come to market. In June 2017, leading experts in cell therapy convened in Philadelphia, PA for the Cell Culture & Cell Therapy: Bioprocessing Conference, and one area of focus was the current state of manufacturing cell therapies. Although work is still needed, cell therapy manufacturing is trending toward more automated, larger-scale, cost-effective processes.
“Over the last 5 to 10 years, the major change in cell therapy—and the one that you’re going to see advancing a little further over the course of the next 2 years—is the focus on the commercialization and the manufacturing process,” Scott R. Burger, M.D., principal of Advanced Cell & Gene Therapy, tells GEN. At the conference, he gave a talk on how to properly manufacture cell therapy products.
Dr. Burger says that the cell therapy manufacturing process has graduated from largely open, manual, individual steps to semi-automated steps that are much more robust and reliable. He uses the term semi-automated because the steps still often require operator input.
“The commercial cell therapies today are being manufactured with semi-automated technology for individual process steps. I don’t mean to make that sound negative—that really is a tremendous advance, and it’s going well—but when we consider the future of cell therapy, we [will] need much more integrated, fully automated processing,” he says.
He notes that companies are already working to automate the process from beginning to end. “The idea is going to be to introduce automation to increase process robustness and dramatically decrease operating costs.”
“Through newly developed and commercially available technology and equipment, cell therapy manufacturing— which incorporates our efforts here at Penn—is moving toward more automated, closed, scalable systems,” Andrew Fesnak, M.D., director of clinical manufacturing development at the University of Pennsylvania, tells GEN. In his talk at the conference, Dr. Fesnak highlighted several newer technologies that have facilitated closed, scalable, automated approaches.
Cell manufacturing stages include apheresis, which is a method for collecting blood cells from the body. “While previous generations of apheresis-collection technology were closed and scalable,” notes Dr. Fresnak, “they were also largely manual processes that required a lot of intervention.” Now, he adds, with newer instruments, there is at least a possibility that automation will be better incorporated.
He explains that further downstream, several of the traditional methods for separating cells of interest—also known as enrichment—are open and manual. Also, he points out, although the process is technically scalable—through the addition of more test tubes—it’s “not necessarily advisable” because risk of contamination increases, too.
The newer enrichment processes, he says, incorporate closed, automated instruments and allow for increased scalability without increased risk. A few newer-age instruments that have been shown in the literature to work for enrichment include the Cell Saver® 5+ (Haemonetics) and the Sepax® system (Biosafe/GE Healthcare).1,2
Another step Dr. Fesnak describes is expansion, during which cell population increases. He explains that the traditional approach to expansion is manual and open, and that while this approach is technically scalable, space constraints may eventually become a problem.
One study from 2016 detailed a procedure in which the time to generate CD19 chimeric antigen receptor (CAR) T cells was reduced from 10 to days to 6 days.3 He notes there are several new products described recently in the literature, from simply designed products, such as G-Rex (Wilson Wolf) and Nunc™ Cell Factory™ systems (Thermo Fisher Scientific), to more complex systems, such as CliniMACS Prodigy® (Miltenyi Biotec) and Quantum® Cell Expansion System (Terumo BCT).4–6
Xvivo GMP System
Kevin Murray, vice president of global sales at BioSpherix Medical, gave a talk at the conference about the Xvivo GMP System, a closed system for processing cells (Figure 1).
“It’s basically a modular design that is constructed around the end user’s protocol of their process. We essentially take everything they would normally do in the open lab and we integrate it and then close it,” Mr. Murray says. The Xvivo GMP System is an alternative to a cleanroom and facilitates aseptic conditions for each cell process. “Cells are essentially in their happy space, so to speak, during the whole production process.”
He explains that in the past decade or so, features such as sensors, data-logging abilities, and software have been incorporated into the Xvivo GMP System to make the system compliant with good manufacturing requirements and best practices.
A closed system such as the Xvivo GMP System has several advantages, one of which is having “superior contamination control,” he asserts. Another is having better process control, which leads to a more consistent product. The third advantage is lower operating costs.
“This industry is going to have to move to closed, automated ways of manufacturing products if it’s going to be cost-effective to make,” he insists.
Bridging Academia and Industry
“Processes developed in academic labs have what people in the field call ‘art,’” Benjamin Fryer, Ph.D., team leader of cardiomyocyte cell manufacturing at the University of Washington School of Medicine, tells GEN.
“You have a specific person in the lab who knows how to make the process work, and they’re the one others turn to if they lack the art themselves. The protocols aren’t often very specific, or if they’re specific, you have to have done it and really understand it,” he says.
Dr. Fryer has been working at the University of Washington on transforming the non-GMP process of making cardiomyocytes in an academic setting into a cGMP, clinical-grade manufacturing process. He gave a talk at the conference about the methods he and his team have been developing.
They have created a five-stage clinical-grade process that spans from the starting cell, which is a pluripotent cell, to the final product cell, which is a cardiomyocyte (Figure 2). The five-stage process is specific to making cardiomyocytes, but, he says, the first three stages, and possibly the fourth, could be used for generally any cell therapy that begins with a pluripotent cell.
Cardiomyocytes are under investigation for their ability to regenerate heart muscle after injury, such as a heart attack. In a study published in Nature, researchers injected human embryonic stem cell–derived cardiomyocytes into the damaged heart of a nonhuman primate, which the investigators showed could remuscularize the heart.7
As for the clinical-grade process he and his team are planning, Dr. Fryer comments, “We’re really trying to take the risk out of the process, simplify it as much as possible, and make it so robust and stable that it can be made by different people around the world in different labs. Ideally, people would always be able to find the components they need.”
Dr. Fryer explains that if one component, or reagent, in the supply chain suddenly becomes unavailable, it could halt production and lead to a backorder. People could end up dying as a result, because they weren’t able to get the therapy in time.
Making a cell therapy is a “significant responsibility,” he says. “When you think about that on the front end, you really want to plan for success.”
Other groups, such as City of Hope in California, are also developing clinical-grade manufacturing processes, he says. “Everyone’s got a slightly different flavor to what we’re doing, but there are many groups that are trying to do that same thing at the same time as us—whether it’s to make heart cells or to make something else.”
1. W.E. Janssen et al., “Large-Scale Ficoll Gradient Separations Using a Commercially Available, Effectively Closed, System,” Cytotherapy 12(3), 418–424 (May 2010).
2. H. Singh et al., “Manufacture of Clinical-Grade CD19-Specific T Cells Stably Expressing Chimeric Antigen Receptor Using Sleeping Beauty System and Artificial Antigen Presenting Cells,” PLOS One 8(5), e64138 (May 31, 2013).
3. T.L. Lu et al., “A Rapid Cell Expansion Process for Production of Engineered Autologous CAR-T Cell Therapies,” Hum. Gene Ther. Methods 27(6), 209–218 (December 2016), doi: 10.1089/hgtb.2016.120.
4. P. Bajgain et al., “Optimizing the Production of Suspension Cells Using the G-Rex ‘M’ series,” Mol. Ther. Methods Clin. Dev. 1, 14015 (May 14, 2014).
5. U. Mock et al., “Automated Manufacturing of Chimeric Antigen Receptor T Cells for Adoptive Immunotherapy Using CliniMACS Prodigy,” Cytotherapy 18(8), 1002–1011 (August 2016).
6. P.J. Hanley et al., “Efficient Manufacturing of Therapeutic Mesenchymal Stromal Cells with the Use of the Quantum Cell Expansion System,” Cytotherapy 16(8), 1048–1058 (August 2014).
7. J.J. Chong et al., “Human Embryonic Stem Cell-Derived Cardiomyocytes Regenerate Non-Human Primate Hearts,” Nature 510(7504), 273–277 (June 12, 2014).