The Future Of Autologous CAR-T Manufacturing: Balancing Innovation With Improvement
By Tyler Menichiello, contributing editor
It’s been seven years since the FDA approved the first autologous CAR-T cell therapy in the U.S. (Novartis’s Kymriah). Today, there are currently six approved in the U.S. (as of September 12, 2024). Despite the ways technological advancements are improving CAR-T manufacturing, two main challenges persist: lengthy production times (vein-to-vein) and patient access to treatment.
While there is a lot of innovation on the product side focused on overcoming these challenges (e.g., Interius BioTherapeutics’ in-vivo CAR-T approach), there is a broader conversation around evolving CAR-T manufacturing from traditional, centralized manufacturing to a more decentralized model, including manufacturing at patients’ point of care (POC).
This was the focus of last month’s Cell & Gene Live event, “Modernizing CAR-T Manufacturing: Is Point Of Care The Future?” The event featured expert panelists Jason Bock, Ph.D., founder and CEO of CTMC, Emily English, Ph.D., SVP and head of manufacturing operations at Cartesian Therapeutics, and Tal Salz, Ph.D., former FDA CMC expert-turned consultant at Dark Horse. Our panelists reflected on the innovations we’ve seen in CAR-T manufacturing, as well as shared their thoughts on the feasibility of decentralized and POC models to address the modality’s manufacturing challenges.
Appreciating Where We Are
With so many new CAR-T products in development, it’s easy to forget just how nascent the modality truly is. “There’s tremendous excitement about CAR-T cell therapy in general, mostly because of the amazing efficacy we’ve seen,” Bock says. Patients who historically had no treatment options are now being treated and even cured of their disease.
However, CAR-T is still very much in the early days, and despite how far it’s come, the panelists all agree: There’s still a way to go for this modality to reach its full potential. “I think we’re just in the first couple innings of this game — maybe even the warm-ups,” Bock says. “We’ve shown that it works, and now it’s a matter of making it more practical,” says Salz.
Innovating The Future, Improving The Present
During the event, there was mutual excitement among the panelists about what the future of CAR-T looks like, especially considering how many companies are pushing boundaries and moving the modality into new therapeutic areas (e.g., solid tumors). “There’s so much innovation happening, and it’s happening so rapidly that I don’t know if we can even really completely envision what the future is going to look like yet, except to say that it’s not going to be exactly the way we started,” English says.
One thing the panelists agree on is that there’s no shortage of opportunities for companies to innovate out of the today’s problems. However, they were sure to note, there’s a difference between innovating new products that address or circumvent these challenges (e.g., allogeneic CAR T, which can potentially address issues related to patient access and manufacturing capacity) and improving on existing processes.
“What I’ve seen the field doing for the last five years is trying to innovate around or outside of autologous cell therapies and investing huge amounts of money in those other areas that have game-changing potential,” Bock says.
The panelists say the market seems to favor the development of new modalities or approaches to CAR-T rather than the improvement of existing, approved CAR-T manufacturing processes. For companies who are either already approved or significantly down the pathway towards market approval, changing the manufacturing process is too complicated, expensive, and time consuming, according to English. “We don’t have great mechanisms to support that,” she says. “The venture space is really focused on new modalities, new indications, and the next sort of bleeding-edge technology that’s essentially, in many cases, unproven.”
While the market may not incentivize smaller and emerging companies to improve on existing CAR-T manufacturing processes, Bock says, larger companies (like Kite Pharma) are in a different position. “Large companies have these technical development groups that can start doing more incremental investment in process improvements,” he says, adding that post-commercial process changes are made possible with funding from the commercialization of these companies’ products.
Shortening The Process
Manufacturing capacity was an important topic of conversation throughout the event. “When we talk about CAR-T, the approved products are all autologous products,” says English, “so we’re in this paradigm of one lot per patient, and that will always throttle the pace at which material can be produced, released, and then delivered to patients.”
Allogeneic CAR-T cell therapies are a promising avenue the industry is exploring to overcome the challenge of limited manufacturing capacity. And while allogeneic CAR-T therapies represent a growing segment in the CGT space, they haven’t yet demonstrated better efficacy than their autologous counterparts — nor have any been approved. Thus, the effort to improve autologous CAR-T manufacturing continues along two primary fronts: shortening the manufacturing process (and consequently, vein-to-vein time) and scaling manufacturing capacity to produce more lots simultaneously.
“People have really been trying to shorten the process,” Salz says. “But unfortunately, there’s biology. Cells have certain expansion kinetics; you have the kinetics of transduction. So, you could innovate within those spaces to try to shorten the process, but at the end of the day, you’d also have to show that it didn’t impact the quality of the product.”
Bock thinks the long-term solution is to evolve CAR-T manufacturing away from reliance on manual labor with the help of advanced technologies and equipment. “Less people, more automation,” he says.
Another way to shorten production time is to simplify product release testing, according to Bock. “Release timing doesn’t get as much attention,” he says. “How can we not only shorten but simplify release testing to make it really value added and not trip us up in the whole release process?”
Can POC Address Today’s CAR-T Manufacturing Challenges?
Towards the end of the event, our panelists discussed the ideas of decentralized and POC manufacturing — two similar models commonly proposed to address the challenges of manufacturing capacity and patient accessibility. While POC isn’t uncommon in the clinical space, it has yet to be tried at a commercial scale. “I don’t think we have enough examples to really, fully understand what POC manufacturing looks like,” Salz says.
The panelists highlighted several concerns around POC manufacturing that explain Pharma’s hesitancy to adopt this model with open arms. Namely, the issue of maintaining product quality from site to site. “There’s an expectation of consistent quality when you have a large company producing a drug,” English says. “With this kind of approach, I think there will be an expectation that you get consistent delivery of quality and efficacy across the board, and I think that’s a challenge.”
There’s also the issue with skilled labor and manufacturing operations. “I think you would have to heavily move towards automation to use the POC model,” Salz says. The most viable POC solution, according to Salz, would be a closed, automated system where a patient’s starting material goes in one side and a ready-to-infuse CAR-T product comes out the other. “Otherwise, you’re going to turn these hospital workers into operators, and then that defeats the purpose,” she says.
Barring this kind of automated solution, most hospitals and academic medical centers lack the GMP-grade infrastructure required for CAR-T manufacturing. “They’re less likely to have robust quality systems, qualified manufacturing facilities, equipment, trained teams — all of those pieces that are part and parcel of executing cell therapy in a commercial manufacturing facility,” says English. For POC to work commercially, “either you have to raise the floor for those places, or you have to lower the bar on the regulatory side, which I think is probably the less likely scenario,” she continues.
Taking humans out of the manufacturing loop seems to be the only viable path towards commercial POC manufacturing, according to our panelists. “I think the true POC conversation almost distracts from what’s realistic in how we’re going to evolve this field,” Bock says. In the interim (i.e., before a hospital-friendly, fully automated manufacturing solution comes around), he says, decentralized or regional manufacturing may be the most appropriate solution.
Whether POC becomes common in the commercial CAR-T space or not, time will have to tell. Nothing will change overnight — the field must crawl before it walks and walk before it runs. Until companies take the risk on trying POC or decentralized manufacturing, the debate will continue in hypotheticals. Like Salz said in her closing statement, “Do it because it makes sense, not because you can.”