Cell Therapy The Engineering Miracle Of Our Times
By Louis Garguilo, Chief Editor, Outsourced Pharma
Vered Caplan, CEO of Orgenesis, Inc., unintentionally grew captivated, and then fully immersed, in our cell-therapy industry.
Her first love, though, is engineering.
Since 2014, she’s been combining the rigors of one with the miracle-making of the second.
“People talk about ‘manufacturing’ cells,” she says. “You don't manufacture cells. What you're doing is engineering and reprogramming cells.”
So based on her engineering principles, Caplan began to look for CDMOs that might be able to help out.
“When we started developing programs, we couldn't find the right subcontractors,” she recalls. “The CDMOs were simply replicating what was being done in the research labs, just at a bigger scale.”
“You know the old saying: ‘How do you build a mechanical horse? You don't, you build a car.’ We needed a different concept altogether.”
Orgenesis ended up acquiring a small lab in Belgium. That lab became the CDMO MaSTherCell.
“We took it as our mission to get these therapies to more patients,” explains Caplan. “We were working with our own products and those of industry partners, trying to gain better quality control, closing up systems, solving those problems.”
Nonetheless, she felt as if they were still treading water by working in the traditional pharma mindset, with its centralized clean rooms, and focus on helping the bigger companies.
At the beginning of 2020, she sold MaSTherCell to Catalent, and began building Orgenesis around a platform solution for its own programs, and to serve even in the smallest of cell-therapy sponsors.
Currently, Orgenesis has 16 programs in its internal pipeline. Where did this diverse lineup come from?
“I ask myself that every day,” Caplan says with a hearty laugh. “We joke we are an orphanage for cell programs.”
Industrial Lag
“This industry is almost magical – reprogramming our own cells for our purposes. It’s not your traditional drug development,” says Caplan. Nor, she says, are traditional biologics-industry approaches suited to the challenges. Cells react to the environment because they are efficient engineering tools. They receive inputs, react to stimuli, and work as a community, she says.
“Cells are also great computers and programmers. If we run algorithms, they know how to react, and adapt quickly,” and so contributing to the possibilities of working with cells – and adding to the complexities – is the data revolution.
“Big data affects our entire life, with information coming from everywhere,” she says.
Our industry’s understanding of “mechanisms” has also improved, including CRISPR and mRNA, along with the knowledge we’ve gained about immuno systems. However, asks Caplan, “How do you utilize cells to become this elegant mechanism for delivering a drug?”
“Because what has not advanced sufficiently is the ‘industrial’ part – taking all that data and turning it into the art of cell engineering.”
Traditional biology has attempted to fill the gap, but “in most cases it's not applicable because you're not really manufacturing. You are reprogramming.”
“And when you enter this world of engineering,” Caplan continues, “you enter a world of more complex systems.”
“Suddenly you’re in a universe of software infrastructure and computational theory. Many of the tools of traditional biotech don't fit this synergistic universe, or help us to replicate quality and effectiveness from place to place.
“In the beginning, what were people using? Cell factories. Simply a whole bunch of stacked Petrie dishes.”
Factories have their place, but won’t provide the cell-therapy developers in need of a new form of industrial support.
If Caplan had to guess, 90% of the cell-therapy industry has originated from clinical researchers, universities, and hospitals trying out therapies for a limited number of patients. These are the organizations and professionals who have approached her since the beginning of her journey.
“Help us make this, or you take it further,” is what they say to Caplan. In some cases, they’ve dosed a handful of patients, but have no way to further scale or replicate.’”
Traditional CDMOs are beginning to adapt service strategies for this blossoming cohort, but new concepts need to emerge.
“The wonderful thing about cells is they are extremely good at getting the job done. If it’s delivering an antibody to the right location, or controlling the level of insulin, they're the best in the world,” says Caplan.
“However, this is not a mindset of let's get a million cells sticking to a gene to make a common protein, then throw away the cells we don’t care about because we just want a certain output.
“This industry is still not about actually preserving vitality and functionality. It’s more about sterilizing products to kill unwanted cells.”
Cell therapy, rather, is “convincing” cells to reliably duplicate or operate, and thus for developers, the challenge is creating environments for this activity.
“I thought the biggest bottleneck would be regulatory, but it wasn't,” says Caplan. “The regulators have been wonderful.”
“I thought the problem would be clinical acceptance; clinicians love these therapies. I thought the problem might be financial acceptance, but look at the reimbursement prices with these products.”
“What became obvious is the bottleneck in this industry is industrialization. How can we make therapies more widely available?”
Enter Engineering
The answer to Caplan’s question? Her engineering concepts.
“Engineering is not only about tools. Considering how to produce a product, the first thing you learn is the cost of that product is the function of its initial design.”
In the beginning, she says, “people were kind of cooking the soup and tasting it. Nobody was talking about things such as in-process controls.”
“Orgenesis is insistent on engineering concepts. Yes, you need incoming material testing, in-process controls, release quality. You also need adaptiveness – quality by design. Transferability so you can produce at various locations. All kinds of engineering concepts that had not been established in this industry.”
Again, CDMOs have gotten better, she iterates. “I think Catalent has done a great job with MaSTherCell.”
“The industry is now incorporating engineering concepts, and serving smaller developers. I want to think we led the way.”
In part two, we’ll learn exactly what that leadership looks like.