Cell therapy

The Food and Drug Administration is easing limitations it imposed around the complex cancer drugs known as CAR-T therapies, removing several onerous requirements as well as loosening restrictions on which facilities can provide treatment.

The FDA’s action applies to therapies made by Bristol Myers Squibb, Gilead Sciences, Johnson & Johnson and Novartis that are used to treat several types of blood cancer. Specifically, it removes so-called “Risk Evaluation and Mitigation Strategies” from the drugs’ labeling, which are used to help manage serious side effects of treatment.

According to the FDA, these REMS requirements are no longer necessary to ensure safe use of these CAR-T therapies as both physicians and hospitals are now well versed in managing the two syndromes most commonly associated with the drugs.

Since the FDA’s approval of Novartis’ Kymriah for leukemia in 2017, six more CAR-T therapies have reached market. These medicines are made from a patient’s own immune cells, extracted from the body and engineered in a lab to hunt down specific proteins found on the surface of malignant clones.

For some people with leukemia, lymphoma or multiple myeloma, they can prompt powerful responses and even long-lasting remission. But their administration also comes with notable risks, including a hyperactive immune response known as CRS and neurological toxicity dubbed ICANS.

When CAR-T therapies were new, physicians and the hospitals they worked at faced a learning curve handling these treatment-associated conditions, which require specific management and drugs to bring under control.

The REMS imposed by the FDA was designed to help mitigate these risks by requiring hospitals receive special certifications before they could administer treatment, and mandating specialized reporting of side effects to the agency.

“Given the established management guidelines and extensive experience of the medical hematology [and] oncology community in diagnosing and managing the risks of CRS and neurologic toxicities across products in the class of BCMA- and CD19-directed autologous CAR-T cell immunotherapies, FDA has determined that the safe and effective use of CAR-T cell immunotherapies for the indicated population can be assured without a REMS,” the agency said in a June 27 statement. BCMA and CD19 are the protein targets of the seven approved CAR-T therapies.

Reporting rates for CRS and ICANS have “remained stable,” the FDA added.

Alongside removal of the REMS, the regulator also reduced its requirement that patients remain nearby the facility they received treatment from one month to two weeks. And its limitation on how long patients must wait before they can drive or operate machinery again after treatment is lowered from two months to two weeks.

Removal of the REMS should lower the logistical hurdles patients face in receiving CAR-T treatment as well as the cost of administration, the Alliance for Regenerative Medicine, a trade group, said in a post to LinkedIn.

“We believe the reduction in CAR-T burden for patients and caregivers, enabled by FDA's new monitoring and driving requirements, will drive expansion of the U.S. cell therapy market,” Daina Graybosch, an analyst at Leerink Partners, wrote in note to clients.

In a statement, Bristol Myers, which sells the CAR-T therapies Abecma and Breyanzi, noted that only two in 10 eligible patients receive the treatments “due to the confluence of complex logistical and geographic barriers affecting patients and providers.”

The changes could help expand use of CAR-T from specialized medical institutions, where it’s most commonly given, to community health centers, Bristol Myers said.

Breyanzi, Kymriah and Gilead’s Yescarta and Tecartus are cleared to treat lymphoma, although Kymriah is more commonly used for leukemia, where it is also approved. Abecma and J&J’s Carvykti are used for multiple myeloma.

The most recently OK’d CAR-T treatment, Autolus Therapeutics’ Aucatzyl for lymphoma, was the first to be cleared without an initial REMS program.

Available cell therapies for cancer aren’t easy treatments to receive. Personalized to each patient, the drugs are complicated and time-consuming to manufacture, and must be delivered and administered on an exacting schedule. And because they come with serious risks, patients need to remain close to the hospital where they were treated for weeks of monitoring.

All of these characteristics make Johnson & Johnson’s choice to roll out direct-to-consumer advertising for Carvykti, a cell therapy it sells for the blood cancer multiple myeloma, somewhat unexpected. The ad, which will air on streaming services like YouTube, Paramount and Roku, is J&J’s first for the drug and a rare instance of DTC marketing for this kind of cell therapy, known as CAR-T.

According to June Lanoue, J&J’s head of U.S. hematology, the company aims to raise awareness about cell therapy, particularly among patients who may not be receiving care from the kind of specialized academic centers where CAR-T is often given.

Carvykti is currently approved in the U.S. to treat multiple myeloma in patients whose disease either relapsed or becomes resistant to treatment after an initial round of therapy. Another CAR-T therapy, called Abecma and sold by Bristol Myers Squibb, is also cleared for this use, but only after two or more prior lines of treatment.

Among these “relapsed, refractory” patients, about half are treated at community oncology centers, Lanoue said. “The actual awareness level of these options is very low,” she added. “In the community, if they’re not able to get it, doctors are not talking about and therefore they don’t have visibility to having a new option.”

J&J’s choice to advertise is a signal of confidence in its ability to manufacture enough Carvykti to meet any rise in demand. Early on in the drug’s launch, production challenges forced the company to limit orders from treating centers. (Bristol Myers ran into similar issues.)

“We feel very confident around production,” said Lanoue. Treatment sites can “order Carvykti without any constraint.”

The launch of the ad came several weeks after the Food and Drug Administration took steps to improve access to CAR-T treatment broadly. The agency eased some side effect reporting requirements and lessened the time it mandates patients stay near their treating facility for monitoring. It also said patients could resume driving or operating machinery sooner after treatment than previously prescribed.

“We think it will give more opportunity to more patients who [live at] a little bit further distance to be able to receive Carvykti,” Lanoue said.

J&J’s 120-second ad introduces a composite patient, “Marvin,” and describes the heavy burden of injections and pills typically used to control multiple myeloma. Carvykti, by contrast, is a one-time infusion that can deliver lasting benefits in some.

Recent follow-up data from an early study of around 100 patients treated with Carvykti showed that, at five years, one-third had not yet experienced disease progression. A story published in June by The New York Times that highlighted these findings led to more patients requesting information about Carvykti, according to Lanoue.

J&J did not share how much it’s spending on this marketing campaign, but Lanoue said it is “significantly less” than what a pharmaceutical company would typically spend on a regular TV advertisement. “This is not a share of voice play; this is ultra targeted,” she added.

Sales of Carvykti reached $439 million in the three months between April and June. The company expects peak annual sales to eventually eclipse $5 billion.

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Anyone looking for evidence of genetic medicine’s enormous promise need only read of KJ Muldoon. The 10-month-old infant headed home from a Philadelphia hospital in June, dressed in a celebratory cap and gown, after his life-threatening disease was successfully treated with a bespoke CRISPR therapy.

While baby KJ is not cured, the treatment has stabilized his disease, a rare liver condition known as CSP1 deficiency, to such extent he’s able to resume eating a normal diet. Doctors, who hurriedly designed and constructed KJ’s custom therapy in a matter of months, have backed off supportive medications and hope he’ll no longer need a liver transplant.

“Each year, 10 million babies are born with one of about 10,000 known rare genetic diseases, many of which are, in principle, now treatable with genetic medicines,” David Liu, a pioneering CRISPR scientist whose laboratory helped in KJ’s treatment, said at a meeting hosted by the Food and Drug Administration.

“The opportunity created by this perfect storm moment in scientific, medical, regulatory and manufacturing innovation is to provide on-demand genetic treatments like KJ’s at scale.”

Yet Liu and 22 other gene therapy experts and advocates who attended the roundtable didn’t travel to the regulator’s headquarters in White Oak, Maryland to extol the field’s advances. By and large, they came to warn of a crisis.

There are now dozens of approved cell and gene therapies in the U.S., some of which offer near-curative potential for serious diseases like spinal muscular atrophy, sickle cell disease and acute lymphoblastic leukemia. However, the sector that’s produced these therapies is struggling.

Investors have soured on genetic medicine as developers struggle to prove they can profitably sell the complex and often hugely expensive treatments. Biotechnology companies are cutting research, laying off staff and, in some cases, shutting down. Large pharmaceutical firms are no longer willing to bet billions of dollars they can surmount the regulatory and reimbursement hurdles that stand in the way of many of these therapies. And academic labs, still bursting with promising new ideas for technologies like CRISPR, now fear their projects will wither on the vine.

“We estimate that over 100 rare disease gene therapy products that had reached clinical stage have been discontinued since 2023 — not because of treatment failure, but because of the risk of market failure,” said Terence Flotte, dean of the University of Massachusetts’ T.H. Chan School of Medicine and president of the American Society of Cell and Gene Therapy.

“The scientific advances that we have witnessed are just nothing short of spectacular. It’s not hyperbole,” said Crystal Mackall, a professor at Stanford University and founding director of the cancer cell therapy center there. “Despite this unconditional scientific success, the field is really struggling to deliver these therapies to all patients who can benefit.”

Their warnings found a receptive audience in FDA leadership. Commissioner Martin Makary and top official Vinay Prasad, who leads the office that oversees cell and gene therapies, were sympathetic to experts’ arguments and pledged to help.

“We are going to continue the successes of the FDA in facilitating the regulatory process for these conditions and these products,” said Makary. “We’re also going to try to improve by creating more efficiencies.”

Prasad, who in the past has criticized the FDA’s accelerated approval of a gene therapy for Duchenne muscular dystrophy, showed support for flexible trial designs and endpoints when appropriate for the disease or treatment.

He also noted the agency accepts that cell and gene therapies don’t always comes with transformative potential. “We understand that progress is not always made in a single leap,” he added. “We will consider incremental steps forward, because those add up.”

The assembled experts came with lists of possible solutions. Carl June, a famed immunologist and cell therapy researcher at the University of Pennsylvania, called for the U.S. to borrow from the two-tier regulatory system used in China, which allows for medical institutions to more rapidly start first-in-human trials under the supervision of local review boards.

Don Kohn, a University of California, Los Angeles scientist who has developed gene therapies, asked the FDA to reduce the requirements for “comparability” testing when companies transition production from academic to commercial settings. 

Others emphasized the importance of regulatory awards, like the priority review vouchers granted by the FDA to developers of certain therapies, who often sell them for needed capital. And many called for the agency to share more feedback and lessons learned from the applications they receive from industry. 

Behind all of their suggestions was a consistent concern: If regulators don’t help solve the field’s problems, the U.S. risks losing its leadership in developing the kinds of treatments that can cure diseases.

“If we don’t adapt, the next generation of treatments will emerge abroad,” said June. “The future of medicine with cell and gene therapy is at stake.”

Their message seemed to be heard by Makary and Prasad, who noted that many of the issues raised are on their radar at FDA. Prasad, for instance, noted that they hope to redact and make available more internal documents to aid developers’ understanding of what the FDA is looking for. 

“This is not a horse and pony show to say we did this,” added Makary. “This is an honest listening session.” 

Struggling cancer cell therapy developer Adaptimmune is backing out of commercial drug manufacturing, announcing in late July it will sell its approved medicine Tecelra and two late-stage assets to US WorldMeds in a deal worth up to $85 million.

The deal is a lifeline for Adaptimmune, which in March initiated a strategic review because of “substantial doubt” about the company’s continued solvency. The transaction will send all employees involved in commercialization and development of Tecelra, as well as the clinical-stage lete-cel and uza-cel, to US WorldMeds.

Per deal terms, Adaptimmune will receive $55 million upfront and could later receive $30 million in additional payments based on achievement of regulatory and commercial milestones. After the sale, Adaptimmune will retain possession of two T cell directed therapies now in preclinical studies to support human testing.

In a regulatory filing, Adaptimmune said that, after the deal, it will cut its remaining workforce by 62% — layoffs that follow a 29% headcount reduction earlier this year that was forecast to save $300 million over four years.

Tecelra gained Food and Drug Administration accelerated approval in 2024 for some patients with synovial sarcoma, a type of solid tumor. It was the first so-called T cell receptor, or TCR, cell therapy approved in the U.S. A half dozen cell therapies that use a different “CAR-T” technology were approved earlier, but have so far only approved effective in blood cancers.

Adaptimmune’s innovation didn’t translate into sales, however. Adaptimmune reported just over $4 million in product revenue in the first quarter of 2025, overshadowed by the company’s nearly $29 million in research and development spending. It held $41 million in cash and equivalents at the end of March.

“After an extensive review of all strategic alternatives available to Adaptimmune we are convinced that this transaction represents the best path forward for Adaptimmune, our patients and stakeholders,” said CEO Adrian Rawcliffe in a statement.

While arguing Adaptimmune’s deal was a “net positive” due to its solvency concerns, Mizuho Securities analyst Graig Suvannavejh wrote in a client note that the size of the deal was “disappointing.” Suvannavejh added that, even with the revenue from the deal and associated cost cuts, “it is still unclear to us [the company’s] liquidity concerns have been adequately addressed.”

Iovance Biotherapeutics has laid off staff in a restructuring that followed a significant cut to its revenue forecasts earlier this year.

A spokesperson in August confirmed Iovance’s plans to reduce its workforce by “less than 20%.” A regulatory filing showed Iovance employed 838 people at the end of last year, though a company presentation last month indicated that number had grown to more than 1,000. Iovance’s workforce will still have more than 1,000 people following the job cuts, which will affect full-time employees as well as contractors, according to the spokesperson.

“After careful evaluation of our long-term goals, operational needs, and resources, we have implemented a strategic restructuring that includes a selective reduction in force to support our mission to innovate, develop and deliver TIL cell therapy to patients in need,” the spokesperson wrote in an email, referring to the type of cellular medicine Iovance specializes in. “This restructuring will extend our cash runway, and we remain on track to deliver on our financial goals.”

In a second quarter earnings report Aug. 7, the company said that 19% of its workforce would be impacted by the cuts. The restructuring will save Iovance more than $100 million annually and enable it to operate through the fourth quarter of 2026. Iovance will also “continue to optimize and refine its cost structure” through what it described as “operational excellence initiatives” over the next few quarters, it said in a statement.

Iovance had about $307 million in cash on hand at the end of June. 

The layoffs come after a slow commercial start for Amtagvi, a cell therapy Iovance developed for an advanced form of skin cancer. Amtagvi is the first marketed cellular medicine made by engineering human cells known as tumor-infiltrating lymphocytes, or “TILs.” The therapy originated from research at the National Institutes of Health in the 1980s and got to market only after decades of fine-tuning, as well as multiple regulatory delays.

Amtagvi was cleared in February 2024 for people whose melanoma progressed after a commonly used immunotherapy or targeted cancer medication. It’s derived from a patient’s tumor tissue in a complex, weekslong manufacturing process. Upon approval, analysts and investors were skeptical of its sales potential, given questions about demand and the complex logistics involved. At about $515,000, the drug’s list price was also at the time the highest of any cell-based medicine for cancer in the U.S.

Iovance initially projected product revenue — which includes contributions from a different immunotherapy called Proleukin — would reach $450 million to $475 million this year. But in May, it cut that forecast by 40%, to between $250 million to $300 million, citing “recent launch dynamics” that had changed its view. In a research note last month, Mizuho Securities analyst Salim Syed noted how prior guidance was modeled on launches from other marketed cancer cell therapies known as CAR-T treatments, whereas the updated projections rely on “real data” from centers actively administering Amtagvi.

Iovance said in its latest earnings report that 102 patients were treated with Amtagvi in the second quarter, equating to about $54 million in sales. Shares fell about 30% as the numbers “were on the lighter side” of the 100 to 110 patients Iovance had anticipated treating, and total product revenue of $60 million missed consensus estimates, wrote Syed in an Aug. 7 note to clients.

Amtagvi could be approved in Europe, the U.K. and Canada this year. It’s also in late-stage testing for non-small cell lung cancer.

Roberto Caricchio has studied lupus for nearly three decades. He’s witnessed steady, but slow, progress in how the frustratingly complex autoimmune disease is understood and treated.

The past few years have been different. Promising early research from a team of German scientists has shown that cellular medicines can drive lupus into remission in ways other drugs can’t. The findings have sparked a surge in industry interest, leading to the start of about a dozen clinical trials. Many more are on the way.

“It’s unprecedented,” said Caricchio, head of UMass Chan Medical School’s rheumatology department. “Sometimes I have to sit down and take a deep breath.”

The latest evidence was on display when leading scientists and physicians in autoimmune disease research gathered in Austria last year for the European Alliance of Associations for Rheumatology’s annual meeting. Georg Schett, whose team at Friedrich Alexander University, Erlangen-Nurnberg in Germany set off the current bonanza, opened the meeting with new results from his team’s study. The data show cell therapy continued to benefit almost all treated participants with several autoimmune conditions. Some remissions have lasted three years.

“I’m very excited,” said Schett, during a press conference. “When we started this three years ago, we did not know where it would go.”

A bevy of companies, including Kyverna Therapeutics, Cabaletta Bio and Novartis, aim to show that Schett’s findings are just the start. At the meeting, they shared updates from clinical studies of these so-called CAR-T therapies in lupus and other autoimmune conditions, like myositis and systemic sclerosis.

The results are from small clinical trials and represent very early steps in what will likely be a yearslong effort to prove these treatments — engineered from a patient’s own cells and proven against certain cancers — can rewire the immune systems of people with inflammatory diseases. They hint at the approach’s potential, but also the high bar drugmakers will have to clear to succeed.

For instance, Cabaletta said that, of the first two people it treated with CAR-T therapy, one no longer needs other drugs and the other is weaning off steroids. Kyverna, which has accumulated the most data of any company in the field so far, reported similar results in six of seven lupus patients given CAR-T, some of whom were treated more than six months prior. Another, with the disease myasthenia gravis, hasn’t had evidence of disease or needed other medications for one year following treatment.

“We are showing that this story about an ‘immune reset’ is taking some shape and form,” said Kyverna CEO Peter Maag, in an interview.

Similarly encouraging responses to CAR-T were reported in other tests by Novartis as well as biotechs iCell Gene Therapeutics and JW Therapeutics.

Across these trials, participants have mostly experienced mild forms of the immune and neurological side effects associated with CAR-T — a relief to researchers as patients’ risk tolerance in autoimmune disease is lower than in people with deadly cancers.

Before beginning testing in 2021, “we were pretty scared by potential safety issues,” Schett, who serves on Kyverna’s and Cabaletta’s scientific advisory boards, said during the meeting. “Now we are much more relaxed.”

Still, effective autoimmune disease treatments already exist, so the bar is higher to introduce cell therapy. And CAR-T drugs remain costly, complex to manufacture and largely only available at specialized treatment centers. It’s unclear whether long-term health issues, such as the secondary malignancies that have been reported in rare cases among cancer patients who’ve received CAR-T, will also occur in people with autoimmune disease.

Cell therapy is “very promising, but I'm not sure that I would use it as my first, second or even third option,” said Daniel Wallace, a lupus expert, professor of medicine and associate director of the rheumatology fellowship program at Cedars-Sinai. He isn’t involved with any of the companies currently conducting autoimmune cell therapy research.

The therapies are only worth it “if we can put somebody who has life-threatening organ disease in remission for years,” he said.

To that end, analysts are watching how well these therapies free people from needing the many immunosuppressive drugs they typically take. At EULAR, Schett revealed one myositis patient relapsed after 18 months of follow-up, while Kyverna said one lupus patient treated with its therapy relapsed after five months. Nine people who received Kyverna’s therapy across trials in different diseases, including that lupus patient, are still on some sort of immune medicine. They have either experienced recurrence or have more advanced disease. In the latter case, it may take longer for CAR-T therapy to show benefit, said Chief Medical Officer James Chung.

Cabaletta reported some symptom improvement in the two treated lupus and myositis patients, but neither are disease free yet.

Wall Street analysts were generally impressed by the results. Jefferies’ Kelly Shi said Cabaletta’s data “fulfilled the goal” of replicating Schett’s results. Thomas Smith, of Leerink Partners, noted the majority of patients treated with Kyverna’s therapy have had a “significant response,” and the numbers could improve with time.

Kyverna claims the one reported relapse was partly due to the lower dose level the participant received. Maag also noted how, in lupus patients, often “multiple things are going on” that require therapy. Some investigators prefer to keep their patients on a low dose of an oral steroid and they are allowed to do so in Kyverna’s trials. With more time, more patients may eventually stop taking other drugs, Maag said.

“Ultimately, the goal is to taper people off of steroids completely,” he said.

“We will have side effects,” said Cabaletta CEO Steven Nichtberger, on a conference call with analysts in early June. “We will have failure to treat effectively in some patients, and that's fine, as long as what we have is at least as good, if not better, than any other company in the industry.”

There are still many unanswered questions about autoimmune cell therapy. Caricchio, of UMass, notes the treatments haven’t been tested in many Black people, who are more likely to have aggressive forms of lupus. He pointed out that people with particularly significant kidney damage, a hallmark of the condition, may not respond as well. And infections observed in testing, while mild so far, bear watching, he said.

Personalized cell therapies are also being joined in clinical trials by treatments made from donor cells or natural killer cells, as well as by dual-targeting antibody drugs called T cell engagers. All are seen as more convenient and easier-to-manufacture options that some analysts think could challenge CAR-T therapy. A similar pattern has played out in oncology, where enthusiasm for CAR-T has been tempered by success with other technologies.

“This is the first CAR-T approach. It’s a proof of concept and shows this can work in systemic autoimmunity,” said Caricchio. “I do truly believe that the next decade will be a life-changing experience for physicians and for patients.”

Abbvie has agreed to acquire cell therapy developer Capstan Therapeutics in a deal worth up to $2.1 billion, the companies announced June 30. 

The acquisition will hand AbbVie access to technology developed by Capstan that uses small fatty spheres known as lipid nanoparticles to deliver into the body genetic instructions able to engineer specific cells. It’s an ambitious scientific approach that blends the science behind CAR-T cell therapy with that of messenger RNA vaccines.

At the time of the deal’s announcement, Capstan was a few weeks removed from dosing the first patient in a Phase 1 trial of its lead drug candidate, which it’s testing as treatment for B cell-mediated autoimmune diseases. Dubbed CPTX2309, the therapy is designed to reprogram immune T cells to target a protein called CD19 that’s commonly found on B cells.

While CAR-T therapies are now well established in cancer medicine, all existing treatments are constructed by removing a patient’s own cells and reengineering them in a laboratory. The complexity, expense and time involved in this process has, for the most part, kept adoption of CAR-T to just a few treatment niches within oncology broadly. 

Researchers have imagined broader usage could come if production of CAR-T was done by the body, rather than by technicians in a lab. This “in vivo” approach requires delivery of genetic instructions to the target cells.

Capstan accomplishes this by using modified lipid nanoparticles and messenger RNA, building blocks similar to the technology that enables mRNA vaccines to train the body to recognize viral proteins. Capstan engineers its lipid nanoparticles to especially seek a certain type of T cell.

In vivo CAR-T could offer a more convenient alternative in oncology, where AbbVie is already working with partner Umoja Biopharma.

But it also could be well suited for applying CAR-T to immune disease. Academic research from several years ago showed CAR-T’s potential treating diseases like lupus and kindled a frenzy of investment from small and large drugmakers alike. Capstan is one of many companies now exploring whether cell therapy might help “reset” the immune system in diseases where the body’s self regulation has come unglued. 

With its drug CPTX2309, Capstan aims to redirect T cells to hunt down B cells that express the CD19 protein. By clearing both pathogenic and normal B cells, the reprogrammed T cells will prompt this immune reset and hopefully prevent disease progression. 

And because T cell reprogramming is accomplished by mRNA instructions, Capstan believes the engineered T cells its treatment creates will be transient and clear out after accomplishing their job.

Prior to the June 30 deal, the biotech had convinced a good number of investors in its approach. Pfizer, Bayer, Eli Lilly, Bristol Myers Squibb, Novartis and Johnson & Johnson all invested in Capstan in at least one of its private funding rounds, through which the startup has raised $340 million.

The acquisition could pay Capstan’s investors up to $2.1 billion at closing. A spokesperson for AbbVie, reached via email, declined to break down the deal’s terms further.

Earlier this year, AstraZeneca paid $425 million upfront to acquire EsoBiotech, which is also working on in vivo cell therapy.