During a recent ASGCT panel discussion, the future of viral vector cell line development was painted as bright ― so what’s holding the next era of gene therapy manufacturing back?
Today’s viral vector workflows have come a long way to help bring life-changing gene therapies to patients in need.
But with research moving at record speeds and a bustling clinical pipeline, scalable and commercially viable manufacturing solutions are needed to deliver on big industry promises. Like the evolution of monoclonal antibody manufacturing that paved the way, ongoing innovation is set to push viral vector production toward more cost-effective and efficient science and technology.
One area primed to disrupt the viral vector space: producer cell lines.
Here, we summarize a recent ASGCT panel discussion where industry leaders point to pivotal cell line changes set to move gene therapy manufacturing into the future ― and the complexities that could be slowing things down.
Producer cell lines sit at the ready for viral vector manufacturing
While transient transfection serves as the current mainstay of viral vector production due to its flexibility and speed, the technology presents cost and productivity challenges, particularly at large scales. Stable producer cell lines (PCLs) have the potential to address these limitations ― are they the future?
“Every year that I’ve been in the AAV [adeno-associated virus] space, it continues to get closer and closer to becoming a reality,” says Paul Herzich, Chief Technology Officer at Solid Biosciences. He went on to highlight yield and product quality as key factors placing producer cell lines in a promising position for the next era of viral vector manufacturing.
While PCLs aren’t currently the industry-standard, there’s a focus on cell line innovation gently pushing production in that direction. “The investment in the science has drastically increased,” said Roman Necina, Vice President, Viral Vectors at Cytiva, further explaining that companies are taking the time to do cell line development work up front and thinking of the end state early. “Once we can get to a high producing cell line, the future is going to be here,” he added.
Bringing producer cell lines into the mix takes time and involves risk
Producer cell lines take time to develop ― time small to mid-sized companies likely don’t have before knowing if their investigational new drug will make it to Phase 2 studies.
Nathalie Clément, Senior Vice President – Vector Development at Siren Biotechnology, confirmed, “It did not make sense at all to invest all of this time and resources before having any clinical data.” Even though a producer cell line wasn’t chosen at the start, changing course is still on the radar for Siren, when the time is right.
But introducing a new cell line mid-way through drives risk. “Sometimes we are risk averse,” said Necina. “We need to make sure we have producer cell lines available where we can build a regulatory pathway moving from a transient cell line to a producer cell line.”
With agencies scrutinizing cell lines, Clément pointed out the value of working with solutions providers like Cytiva and a cell line with a defined history to reduce overall risk. “Don’t develop your own cell line,” she said. “When you’re ready to do PCL, you go to the experts.”
Comparability studies rule when changing to a producer cell line
Comparability is a hot topic when transitioning from transient transfection to producer cell lines, as regulators will want to see that a PCL-based process maintains your product’s defined critical quality attributes.
“Every comparability exercise is a risk-based analysis of what changed,” said Jacob Smith, Head of Tech Development and CMC at Viralgen, before highlighting the complexity of comparability for viral vectors. Data sets are growing, analytics are advancing, and the industry is still defining what attributes are actually important for AAV products.
Demonstrating comparability can drive decisions around transitioning to a producer cell line. “I would want to do this pivot to PCL before Phase 2 if possible, just to simplify my comparability studies across the phases,” Clément explained.
Herzich said Solid Biosciences is looking to make the shift to PCL later in the clinical journey, but the company is going in with an understanding of what regulators will need. “We’ll have a good data set on transient to be able to compare back to our PCL post-commercialization and have a really in-depth comparability package to be able to bring to the agency when we’re ready.”
Cell lines are key to advancing gene therapy manufacturing
A continued focus on innovation in cell line development is sure to lead to more efficient and effective viral vector workflows, and transformative leaps in technology ― like producer cell lines ― can drive big change.
Still, the gene therapy industry probably shouldn’t look to a one-size-fits all fix or lose sight of the value of iterative, incremental improvements. As Smith highlighted, early proof-of-concept data are often enabled by the accessibility, agility, and consistency of transient transfection. “That doesn’t mean we can’t push for innovation,” he added. “There’s a fixation around producer cell lines, and there should be.”
Whether panelists represented a CDMO, gene therapy developer, or solutions provider, the sentiments across the board were similar. As Smith so simply put it, “We’re all sort of here for the same reason, which is improving accessibility to potentially transformative therapies.”