Cell therapy reckoning: How to get cell therapies flying off-the-shelf

This story is the final part of a four-part series about cell therapy created by the Fierce Biotech team. Gabrielle Masson, Helen Floersh, James Waldron and Max Bayer contributed reporting to this series. Part 1 is here, part 2 is here and part 3 is here

The trouble with cell therapy is that it's not a pill or an injection. It isn't one single product that can be packaged up to await use on a pharmacy shelf, like the industry is typically used to. 

So if companies do succeed in collecting the clinical data to drive into autoimmune, they will still face a key challenge that has dogged the earlier entrants to the markets: manufacturing. For all the promise of “off-the-shelf” cell therapy, the currently approved options still aren’t allogeneic. And they do not exist in the same domain as small molecules or injectable biologics.

“They're still not products. They're still procedures, right? We sometimes forget about that. But these are not pharmaceuticals,” said Eric Schmidt Ph.D., biotech analyst for Cantor Fitzgerald, in an interview.

“Every single individual is the drug,” said Cindy Perettie, global head of Gilead’s Kite Pharma unit.

To receive Gilead’s approved autologous therapy Yescarta, patients have their cells collected and then shipped back to the manufacturing facility, where they are turned into CAR-T cells. In the meantime, patients receive chemotherapy to prepare. The CAR-T cells are then infused back into the patient with a one-week hospital stay. After discharge, patients have to stick close to the hospital for as long as a month before going home.

Schmidt sums it up: the products are unpredictable, even with the best data.

“That process takes time, it's idiosyncratic to the patient. It can be thrown off course by things that you can't control, by human beings, by biology by manufacturing,” Schmidt said. “It's not a modality, it's a treatment regimen.”

Perettie's team at Gilead has been working hard to make the process even faster. “We have our turnaround times at 14 days and we have line of site to 10,” she said, adding that the goal is to have patients be seen by their doctors every two weeks. 

Nevertheless, Gilead has managed to build a successful franchise, thanks to Yescarta's efficacy. 

“It just works really well. There's no competition and the profile is terrific,” Schmidt said.

But Perettie knows Kite has to do more to reach everyone who needs it. Currently, just two out of 10 patients have access to cell therapy in the U.S. And there are major inequities in the demographics who have received treatment, with the vast majority of patients identifying as white, according to a 2022 study.

“Somebody in rural Tennessee doesn't want to fly to New York for a treatment and have to spend 30 days near the center they've been treated. And so how are we bringing it into the community?” Perettie said.

Cell therapy is expensive to develop and administer. The list price for Breyanzi was around $410,000 when it launched in 2021, while Yescarta is priced at about $424,000 per infusion. 

“Let's be honest, I mean, these are not cheap therapies to develop. It's a very capital-intensive pursuit,” said Allogene's Zachary Roberts, M.D., VP of R&D and chief medical officer.

The approved products have shown that the logistics of transportation to and from hospitals is really difficult, even with the biggest pharmas behind the effort, said Sami Corwin, Ph.D., a research analyst at William Blair. “That's quite a heavy lift.”

And the manufacturing challenges emerge early in the biotech life cycle, when companies have to fight for every dollar. Investors are often unwilling to pitch in cash to an idea like manufacturing in early fundraising rounds.  

"It's not sexy but it's very important," said FDA’s Peter Marks, Ph.D., director of the Center for Biologics Evaluation and Research (CBER), at the American Society of Gene & Cell Therapy conference in Baltimore earlier this month.

But the FDA has been crystal clear that companies must use the intended market product during clinical trials, even going so far as threatening clinical holds for not doing so. Marks said this threat, which appeared in recent guidance on CMC for cell therapies, will hopefully “move the needle” to get biotechs—and investors—thinking about manufacturing early on in the process.

He noted that the agency has to help support the development of potency assays that can show the product can be made safely for every patient.

“I think we probably are missing out on several products that would be very valuable to human health because people don't realize how important that is in developing them. Not having a potency assay means you don't have control on a process well enough to be able to make the same thing time after time," Marks said.

“Companies are taking a step back ... and realizing how challenging that is, and maybe saying, Okay, well, maybe that's not what I want to invest in right now,” Corwin said.

Where does the science go?

For Bristol Myers Squibb, which is undergoing "a strategic productivity initiative" to achieve $1.5 billion in cost savings by the end of 2025, the move to shut down the California research center was not an indication of disinterest in cell therapy. The ultimate goal is to reinvest money back into innovation, a spokesperson for the company told Fierce Biotech.

"Bristol Myers Squibb remains one of the largest cell therapy companies in the world, with the broadest cell therapy pipeline of any company in the industry," the spokesperson said, adding that the cuts to the Cell Therapy Organization will "streamline and focus efforts on the most promising areas." 

"Bristol Myers Squibb will continue to be a top investor in the science behind cell therapy because we believe in the transformational nature of this modality and our unique position to lead this field," the spokesperson said. 

Regeneron just dug deeper into cell therapy with the acquisition of 2seventy bio’s cell therapy portfolio for $15 million earlier this year. Phil Gregory, head of Regeneron Cell Medicines, still believes there is plenty of opportunity in cell therapy.

“Regeneron in general has shown—I'm not gonna say it's a disregard—but at least they're uninterested in the trends right now,” Gregory said in an interview at the American Society of Gene and Cell Therapy meeting in Baltimore earlier this month. “They're interested in where is the science leading us and where are we going to get to most transformative outcomes.”

He added: “We're not really too bothered about what other people are doing.”

If biotechs can finally crack off-the-shelf allogeneic CAR-T, which can be more scalable and more easily manufactured, Corwin believes companies who have made the jump to autoimmune may find themselves a market after all. They also could draw in the Big Pharma players. 

The cost of developing cell therapy has sent biotechs scrambling to ink partnerships with Big Pharma, a natural move in such a tough funding climate, according to Roberts.

“This takes a lot of investment in infrastructure. And so you can get to a certain point with these exciting targets, but if you can't scale globally, it's really hard to deliver a therapy like this,” Perettie said.

If the target in autoimmune is initially on more severe patients who frequently relapse, Perettie said that won’t be a huge lift for smaller companies. But those trying to do both oncology and autoimmune may quickly run up against the realities of the biotech business. And if the indications tip toward larger patient populations like lupus or multiple sclerosis, then smaller companies are going to struggle to meet the challenge.

While the big focus at Regeneron right now is integrating the 2seventy assets, Gregory hinted that the Big Biopharma could be on the hunt for more external partnerships once that work is complete.

BMS, too, is eyeing autoimmune for opportunity, the company spokesperson said. 

"As an industry leader, we are laser-focused on delivering best-in-class and first-in-class treatments in our approved indications across blood cancers while simultaneously exploring opportunities to bring the promise of cell therapy into new frontiers, including autoimmune diseases," the BMS spokesperson said. 

Meanwhile, Cartesian is putting more money into manufacturing, with the recent acquisition of a 20,000-square-foot facility in Frederick, Maryland for phase 3 commercial activity. That will allow the biotech to prep all the product for late-stage trials and the commercial market later on. The company now has a total of 27,000 square feet of manufacturing space.

“For us, it's not a pullback. For us it's expansion,” said Miloš Miljković, M.D., Cartesian Therapeutics' chief medical officer.

And over at Kite, Perettie's team is working on developing a more community-based practice through a collaboration with Tennessee Oncology, bringing the pharma’s cell therapies to rural patients who need it. Other programs are happening in Texas and Florida. But she says other companies need to get involved too.

“They know these therapies are going to cure patients, and they want them for their patients,” Perettie said of rural practices. “You have to have that mindset and that's why bringing the ecosystem together has to happen. And it's going to take every single CAR-T company to lift this.”

Perettie sees a successful allogeneic approach as a potential key.

“I hope it makes it,” she said. “Because you could scale to the masses and bring it to countries that may not have infrastructure and capabilities … but it hasn't panned out yet.”

Which leads her to this: “And so the question is, will it be enough in autoimmune?”

Creative thinking

Roberts is not deterred by all the upheaval and unanswered questions in cell therapy but instead sees this moment as a natural step towards eventually finding the right path for the technology.

"Maybe we're witnessing a reshuffling, if you will, of how that work is getting done. But certainly no, I wouldn't call it a divestment or anything other than that,” he said. Instead, the industry is finding new ways to conduct clinical trials and get through the regulatory process. He pointed to the recent advancement of cell therapy in solid tumors and the recent gene therapy approvals as examples.

The packaging for Bristol Myers Squibb's Breyanzi in mantle cell lymphoma (Bristol Myers Squibb)

“I would say the momentum is as strong as it was even 10 years ago,” Roberts added. 

If you ask BMS, that's certainly true. Just yesterday, the company received an FDA approval for Breyanzi in mantle cell lymphoma. 

The team at Poseida is also planning a slow rollout in autoimmune to ensure they go after the right indication with the right science backing them. 

"Though our allo CAR-T pipeline is currently focused on oncology, we are actively working on an autoimmune strategy and believe that all of the advantages our platform has in oncology are likely to play equally as well in autoimmune disease. What we want to make sure that we are doing is doing it in a mindful way because for our programs in oncology, the approach is working, the data looks great. We are looking at this opportunity and we are going to be strategic, thinking very carefully about the right cellular target, the right disease state and the right entry approach," CEO Kristin Yarema, Ph.D., said in an email to Fierce Biotech.

Niche markets may be just where biotech needs to play in these uncertain times.

“That's where the field needs to go,” Roberts said. “I would just hope that the field as a whole begins to think super creatively about how best to deploy those assets. Because there's just a ton of opportunity out there.”