Cell therapy

The clue came, as they often do, from an unexpected source. Two years ago, a small study of five people in Germany pointed to a new direction for the high-profile field of cell therapy.

The study showed a cellular medicine could drive a tough-to-treat form of lupus into remission. While early, the finding suggested a technique used to create powerful cellular treatments for cancer might also work against autoimmune conditions like lupus, too.

“It’s very early days, but it’s exciting for the field to see this possibility,” said cell therapy pioneer and University of Pennsylvania immunologist Carl June, in an interview at the time.

The biopharmaceutical industry took note. Since the paper was published, a number of drugmakers have revealed plans to develop cell therapies for lupus, and a dozen or so are now in clinical testing.

Updated results from that German study, presented at a medical meeting in December 2023, indicate they may be right to invest. Among 15 people who had lupus or one of two other autoimmune diseases and hadn’t responded to prior treatment, all were in remission after receiving cell therapy. Some responses have lasted two years.

“It’s the tip of the iceberg, but it looks extraordinary,” said Andy Plump, Takeda Pharmaceutical’s head of research, in a recent interview. “The hope is that this can expand to not just other refractory autoimmune diseases, but to more common diseases.”

Challenges remain. Current cell therapies for cancer are associated with side effects that in rare cases can be fatal, a risk that’s easier to accept for people with deadly tumors than those with chronic health conditions. They’re also complex to produce and administer, and only available at major treatment centers, limiting their potential for wider use. Some believe newer “off-the-shelf” alternatives may be a better fit.

Answers could come within the next few years from clinical trials just getting underway. At least a dozen studies run by startups, biotechnology companies and large pharmaceutical giants are either recruiting participants or soon will be. Here’s where the field stands:

How is lupus treated now?

Lupus is a chronic autoimmune condition that occurs when the body attacks itself. The disease leads to pain and inflammation in many parts of the body, from the skin and joints to internal organs like the kidneys or lungs. About 1.5 million people in the U.S. and 5 million worldwide have a form of the disease, according to the Lupus Foundation of America, a patient advocacy group. For reasons that aren’t quite clear, many of those affected are women of childbearing age. Researchers aren’t certain what triggers the disease in the first place, either.

Lupus has several types, the most common of which is known as systemic lupus erythematosus, or SLE. It affects multiple organs and can involve a constellation of symptoms, making it tough to diagnose. Lupus’ characteristic ‘flares’ arrive unpredictably and can last days or weeks. While most people can manage their disease and live a long life, the condition can result in kidney failure or death from heart-related complications.

There is no cure. Available treatments can help manage symptoms and counteract the immune response associated with the disease. They include repurposed anti-inflammatory or immunosuppressive therapies, steroids or antimalarials.

More recently, three medicines specifically developed for lupus — GSK’s Benlysta, Aurinia Pharmaceuticals’ Lupkynis and AstraZeneca’s Saphnelo — have reached market. Roche’s cancer drug rituximab is sometimes used off-label as well, despite disappointing clinical results.

All have limitations, however. Not everyone responds to treatment and patients can continue to have flare-ups, requiring them to try different treatments. Additionally, drugs that blunt the immune system, like steroids, can leave patients vulnerable to infection.

How could cell therapy be used?

Six so-called CAR-T cell therapies are approved in the U.S. to treat leukemia, lymphoma and multiple myeloma. When they work, these therapies can lead to long-lasting benefit.

They’re made by genetically modifying a patient’s immune cells to spot proteins found on the surface of cancerous B cells. These cells, which normally make protective antibodies, are also implicated in an array of autoimmune diseases. In lupus, for example, B cells go haywire and make antibodies that damage healthy tissue.

CAR-T therapies wipe out B cells, whether cancerous or not. That effect led Georg Schett and colleagues at the Friedrich Alexander University, Erlangen-Nurnberg, to test CAR-T therapy in people with lupus.

Schett’s team published a case report in The New England Journal of Medicine in 2021, following up one later with results in four more study volunteers, which were presented in Nature. They found the drug depleted B cell counts and drove participants’ disease into remissions that persisted without using other drugs.

Notably, treated individuals still responded to vaccines and their levels of infectious disease antibodies “largely remained intact,” wrote analysts at the investment bank William Blair, in a recent report. Side effects were mild.

When B cells did regenerate, disease symptoms didn’t return, which the authors suggested could support the idea that CAR-T therapy “reboots” the immune system.

To drugmakers, the findings indicate cellular therapies, if engineered right, could potentially cure some autoimmune diseases.

“There's a huge potential for patients to really benefit,” said Samit Hirawat, the chief medical officer of Bristol Myers Squibb, in a recent interview.

Yet it’s still unclear how long responses will last, or whether people may need to be re-treated later. The results may not be replicated as CAR-T therapies are studied in large groups of people with lupus, either.

CAR-T also involves a chemotherapy “conditioning” regimen to prepare patients for therapy. And treatment can cause serious immune and neurological side effects that, in an autoimmune disease setting, “will not be acceptable to patients and physicians,” wrote William Blair analysts.

More seriously, the Food and Drug Administration recently issued safety warnings for all six available CAR-T therapies, following a review of reports of patients developing secondary malignancies after treatment.

Those risks will require developers to mitigate CAR-T’s known safety issues. Companies working on adapting the therapies say their goal is to fine-tune the approach for use in autoimmune diseases.

“I think the whole industry is asking: how can we work on the benefit-risk profile and the conditioning process so that, ideally, you can [treat patients] earlier and earlier and not wait until they have severe, refractory disease?” said Victor Bulto, head of Novartis’ U.S. division.

Which companies are working on cell therapies?

About a dozen companies have launched trials testing cell therapies in lupus, according to a federal database. At least another six have received Food and Drug Administration clearance to begin initial studies and could soon follow, while others still have disclosed plans for testing.

Two cell therapy leaders, Novartis and Bristol Myers Squibb, started Phase 1 trials last year. They’re each testing newer versions of the products they brought to market for cancer, tweaking them to cut manufacturing times, boost safety and raise potency.

Bristol Myers’ Hirawat noted how Schett’s research suggests developers can deliver benefit in lupus with lower and, theoretically, safer doses than in cancer. That’s partly because there are fewer B cells to target in lupus than there are cancerous cells in lymphoma or leukemia.

“We don't anticipate, or want to see, the same safety profile as you saw in malignancies,” he said.

Alongside Bristol Myers and Novartis is Kyverna Therapeutics, a well-funded biotech startup that went public in February. Kyverna’s lead program was licensed from the National Institutes of Health and, like that of its larger rivals, targets the protein CD19.

Also in testing are Gracell Biotechnologies, which AstraZeneca acquired last year, Cartesian Therapeutics and startups Cabaletta Bio and ImmPACT Bio. Behind them are an array of cell therapy companies that have said they will go after lupus and other autoimmune diseases, like Fate Therapeutics, CRISPR Therapeutics and Autolus Therapeutics.

China-based biotechs and academic researchers are investing in lupus research, too. A federal database shows nearly a dozen academic or industry-backed trials underway, including studies run by JW Therapeutics, Shanghai GeneChem and Chongqing Precision Biotech.

Some that haven’t publicly announced trial plans, like Takeda, are interested: “Even though we're very far behind, we still think that we have a path,” Plump said.

One reason: Not everyone is pursuing the same approach. Some companies have cell therapies that target BCMA, another protein on B cells, as well as CD19. Some are looking at different targets. And others are changing out components to boost potency, or are tweaking conditioning regimens.

Meanwhile, companies like Artiva Biotherapeutics, Fate, and Sana Biotechnology are trying approaches that rely on the cells of healthy donors. These so-called allogeneic treatments have struggled as cancer therapies. But some developers claim they may have an edge over personalized, or “autologous,” treatments in autoimmune conditions. Here, they say, the advantages of donor-derived therapies like cheaper production costs or lower rates of side effects will be more important.

“Autologous cell therapy for autoimmune [disease] is going to be pretty challenging,” said Carlo Rizzuto, managing director at Versant Ventures, a venture firm that invested in allogeneic cell therapy developer Century Therapeutics. “I do think that allogeneic off-the-shelf approaches, especially the stem cell-based approaches, will have an advantage.”

Cell therapies could also face competition from newer antibody drugs designed to better deplete B cell counts. Roche and Johnson & Johnson, for instance, have drugs in mid- or late-stage testing for lupus.

“We will have to see how science evolves across all these modalities and see which one works best for which patients,” said Bulto, of Novartis.

What’s next?

Several clinical trial readouts this year and next could build on Schett’s study. The tests underway are enrolling patients with SLE or lupus nephritis, when the condition affects the kidneys. Some developers are recruiting people with other autoimmune conditions as well, which could provide more clues as to how broadly cell therapy might be applied.

Kyverna presented early results from a lupus nephritis study last year and is recruiting patients. A fuller readout could come in 2025, according to a federal database. The company is planning to test its treatment in systemic sclerosis, myasthenia gravis and multiple sclerosis, too.

Novartis shared preliminary findings last year in a study testing its therapy, YTB323, in SLE. More data are expected in the second half of 2024. Bristol Myers should provide an early look at its program’s potential this year, too, and intends to expand into MS, myositis and other conditions.

Others, such as Fate, Nkarta and CRISPR intend to start dosing patients in 2024. Startups with different approaches, like Luminary Therapeutics, could follow afterwards.

Some of these efforts will need to bear fruit for investment to continue at such a torrid pace. CAR-T’s potential in lupus alone “can't sustain this massive energy” in the industry, Plump said. “There are pieces that we're just starting to work through, but it's an area of a lot of excitement.”

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 in early June, when leading scientists and physicians in autoimmune disease research gathered in Austria 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 June 17 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 new 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 ago. 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 on June 17. “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.”

Artiva Biotherapeutics in mid-July raised $167 million in an initial public offering centered around the promise of donor-derived cell therapies for autoimmune diseases.

Artiva sold 13.92 million shares at $12 apiece, securing more money than it expected but at a lower per-share price than it had outlined earlier. The bulk of the proceeds will fund a treatment made from “natural killer,” or NK, cells and that is currently in early-stage testing in lupus and other inflammatory conditions.

The offering came two years after Artiva canceled an IPO proposal showcasing cancer cell therapies, from which it later pivoted to autoimmune disease research. It also followed days after a paper published in the journal Cell showed what analysts described as early proof of the potential for donor-derived treatments in autoimmune disease.

Artiva’s IPO was a test of investor faith in the recent repositioning of so-called allogeneic cell therapies, a type of medicine harvested from the cells of donors.

Allogeneic therapies are seen as more convenient than treatments made from the immune cells of individual patients. But they’ve struggled to prove their worth in oncology, where developers have had difficulty matching the long-lasting benefits reported in testing of personalized, or “autologous,” cell treatments.

Several allogeneic companies, including Artiva, have since redrawn their development plans, believing that autoimmune diseases may be a better fit for the technology. Recent academic research has suggested cellular medicines may be able to drive a variety of inflammatory diseases into remission in ways other drugs can’t, leading to a rush of autologous programs advancing into human trials. But production complexities, high costs and safety concerns associated with autologous therapies may be less acceptable in an autoimmune disease setting.

Allogeneic cell therapies, by comparison, are cheaper to manufacture. And one of their key weaknesses — that they often don’t last very long in the body — may not be as much of an issue in autoimmune disease, where a therapy’s objective is to quickly wipe out malfunctioning B cells so a “reset” can take place.

Earlier in July, BRL Medicine, a privately held, China-based biotech, provided the first signs in a human trial that donor-derived treatments might be able to achieve that goal. A paper its scientists published in Cell showed an experimental allogeneic therapy provided benefits lasting as long as six months in three people with either myositis or systemic sclerosis. Though the sample size is very small, the findings provide “early validation for off-the-shelf cell therapy” approaches, wrote Leerink Partners analyst Daina Graybosch in a client note.

Graybosch and other analysts at Jefferies and William Blair think that validation extends not only to developers of T cell-based treatments, like Allogene and Poseida Therapeutics, but potentially to those like Artiva that specialize in NK cell therapies as well. Shares in several climbed following the paper’s publication.

Artiva expects initial results from a “basket” trial in multiple inflammatory conditions next year.

Candid Therapeutics, a new biotechnology startup with plans to develop antibody drugs for inflammatory diseases, debuted Sept. 9 with more than $370 million in funding.

The startup amassed its pipeline by buying two private biotechs, Vignette Bio and TRC 2004, that had recently acquired rights to cancer drug prospects from China. Candid now owns rights to those drugs — a pair of so-called T-cell engagers — and should start its first clinical trials in inflammatory conditions next year, said CEO Ken Song.

Candid raised $206 million on its own and, through the merger, now also has the $165 million in combined funds previously secured by Vignette and TRC 2004, according to Chief Financial and Business Officer Arvind Kush. The funding enables the company to operate for several years and be “opportunistic” in pursuing a potential initial public offering, added Song, whose previous company, RayzeBio, was acquired by Bristol Myers Squibb in December.

Candid’s launch is indicative of how growing interest in cell therapy for autoimmune diseases has expanded to include T cell engagers, too.

Research from scientists in Germany showed that cellular medicines can lead to lengthy remissions for certain chronic conditions by wiping out malfunctioning B cells. More than a dozen clinical trials testing autoimmune cell therapies have since begun. Others could soon start as well.

Song has paid close attention. After selling RayzeBio to Bristol Myers, he formed a shell company, Candid, staffed it with a management team and searched for drugs to build a biotech around. He found the cell therapy research captivating, but mostly because it provided a blueprint for a therapeutic strategy that could have “transformative” impact, he said.

In Song’s view, cell therapy is ill-suited to deliver that impact. Between high production costs and the need for chemotherapy-based preparatory regimens, “I never really felt that cell therapy would be a commercially viable approach” for autoimmune disease, he said.

Song instead believes T-cell engagers, or dual-targeting antibody drugs, are a better solution. He approached Vignette and TRC 2004 while they were cutting deals for two such candidates, and convinced them to have Candid’s team develop those drugs under one roof.

Like cell therapies, T cell engagers can be designed to target B cells. But they’re administered more conveniently, don’t require chemotherapy conditioning and are easier to manufacture. The approach has shown promise this year, too. Case reports published in the European Journal of Cancer and The New England Journal of Medicine describe encouraging results in autoimmune disease patients given T cell engagers typically used for cancer.

A handful of companies have already shown interest. Roche has two medicines in early testing. Cullinan Therapeutics and IGM Biosciences are starting trials. Zenas Biopharma, which filed to go public recently, is also in the mix. And Merck & Co. recently paid $700 million to acquire a drug it sees as having potential in several inflammatory conditions.

All of these projects are early. T cell engagers haven’t yet proven they can be as effective as cell therapy in autoimmune disease, or deplete B cell counts as thoroughly. “We’re still at the starting line,” Song said.

Candid, though, bets it can catch up. The two drugs it licensed have completed Phase 1 testing in cancer indications and should be ready in 2025 to begin trials in people with autoimmune conditions. The two drugs target different proteins — BCMA and CD20 — on the surface of B cells. Candid expects to add more to its portfolio in the future.

“I think it is really just a matter of time before the industry at large comes to realize that T cell engagers are probably the right horse to bet on [for] autoimmune disease,” Song said.

Investment in developers of cell and gene therapies nosedived through the first half of 2024, a sharp drop-off that investors and analysts say reflect manufacturing and drug delivery challenges at a time when biotechnology companies with clear development paths are increasingly favored.

Through late summer, makers of cell and gene therapies raised half of a billion dollars across 16 venture rounds, according to data from DealForma published by Nature. Even annualized, those numbers are well below the $8.2 billion in funding brought in by the 121 deals DealForma counted during the sector’s peak in 2021. Last year, cell and gene therapy developers raised $3.5 billion across 65 deals.

“We’re largely seeing investments shifting to things that are de-risked,” said Jon Norris, a managing director at HSBC Innovation Banking. “Cell and gene therapy is becoming an area we know better, because there are products that have advanced through development, but it still doesn't compare to the number of approvals and drugs commercially available in small molecules or biologics.”

Overall, biotech venture investment higher over the first half of 2024, according to a mid-year report from HSBC Innovation Banking. Yet, regardless of technology or research field, biotechs still face a challenging financing environment.

Developers of cell and gene therapies face additional hurdles, however, “given that the kind of capital required to advance these therapies is different from small molecule drugs or biologics,” said Peter Sletteland, a managing director for Silicon Valley Bank’s life science and healthcare practice. “You typically need to spend significant investment in manufacturing.”

Still, he added, cell and gene therapies “garner a lot of attention because of the promise of what they could do.”

Six CAR-T cell therapies have been approved by U.S. regulators to treat cancer and, in some indications, their benefits can be dramatic. But hopes of replicating that success with so-called allogeneic therapies, which use donor cells rather than individual patients’, has been harder to come by than initially envisioned by investors. And uptake of some of the approved CAR-T therapies has been slow, especially as companies work through manufacturing bottlenecks.

In gene therapy, sickle cell treatments Casgevy and Lyfgenia secured milestone approvals from U.S. regulators late last year. But only a few dozen patients have begun the process to receive treatment, reflecting the long manufacturing and infusion times needed for each.

Adoption has also been slow for the hemophilia gene therapies Hemgenix and Roctavian, while other gene therapy developers like Pfizer have hit clinical setbacks.

Patient perception of gene therapy is a crucial barometer. "The therapy has to be worth it, but the question is, are there treatment alternatives?" said Chris Bardon, co-managing partner at MPM BioImpact.

For diseases that have limited treatment options, it may be easy for a patient to consider an intensive cell or gene therapy treatment, which can require arduous chemotherapy preconditioning. But such treatments may by less appealing to people with conditions that are manageable with approved medicines, such as is the case in hemophilia.

"It has been a challenge for investors," Bardon said.

The challenge of developing and selling cell and gene therapies, though, isn’t enough to deter investors and drugmakers entirely.

In cell therapy, for instance, there’s buzz around the potential to target hard-to-treat autoimmune disorders, said Bruce Levine, a cell and gene therapy pioneer at the University of Pennsylvania who co-founded Tmunity Therapeutics and Capstan Therapeutics with colleague Carl June.

“That's the nature of a therapy that, currently, through the cost of goods and services, is expensive to manufacture, but delivers long-term, durable benefit in patients who have failed all other available therapies,” Levine said.

The Food and Drug Administration has cleared two multiple myeloma cell therapies for earlier use treating the blood cancer, granting expanded approvals to Bristol Myers Squibb's Abecma and to Johnson & Johnson's Carvykti.

The OKs come three weeks after a panel of FDA advisers agreed the benefits of earlier treatment outweighed the risks, including concerns raised by agency reviewers over data indicating an elevated chance of death among treated study participants early on in the companies' main trials.

Abecma, which is co-marketed by 2seventy Bio, is now available for people who previously received at least two drug regimens for their multiple myeloma, while Carvykti can be used after just one prior line of therapy. J&J developed Carvykti together with Legend Biotech.

Overall, trial results showed that both Abecma and Carvykti substantially reduced the risk of disease progression or death, compared to standard regimens. But the safety concerns raised by the FDA were enough to put Friday's approvals somewhat in question.

Seeking advice, the FDA in mid-March convened an expert committee to debate earlier use of the therapies. Ultimately, they found the benefits of both to be substantial enough to look past the early death risk raised by the FDA, voting 11-0 in favor of Carvytki and 8-3 in support of Abecma.

In responding to the FDA's concerns, Bristol Myers had cited patient crossover from the control arm to treatment as confounding survival data. The advisory panel also noted complications with the “bridging” therapy used prior to CAR-T treatment, which may be different in clinical practice than in a trial.

Treatment benefit “is significant and offers our patients a chance of significant time off therapy with associated quality of life improvement,” said Christopher Lieu, a panelist and associate medical professor at the University of Colorado, at the March 15 meeting. “But it’s a closer margin than I think we would like, and patients will need to have in-depth discussions about the risks and benefits.”

Both therapies target a protein called BCMA that’s found on malignant B cells in people with multiple myeloma. Their earlier approvals for later-line treatment added another option to a growing arsenal of therapies that have helped improve outcomes for patients with the blood cancer.

Still, people with multiple myeloma often relapse or their cancer becomes resistant to one treatment, requiring a switch to different regimens.

Abecma was previously cleared for relapsed or refractory disease in adult patients who have received four or more prior regimens, including ones that involve three of the main classes of multiple myeloma drugs.

Now, Abecma can be used in after two lines of therapy, provided patients are “triple class-exposed,” or have received treatment that includes those three types of drugs.

Carvytki can be used even earlier, as soon as after a patient's first relapse. The label specifies treatment for people who have received at least one line of therapy that includes a so-called proteasome inhibitor and an immunomodulatory drug. Patients' disease must be resistant to treatment with a drug called Revlimid.

"This product label difference offers significant commercial advantage for Carvykti as its eligibility for use in [second-line multiple myeloma] patients should limit the use of other BCMA CARTs in the following lines of therapy," wrote Jefferies analyst Kelly Shi in an April 7 client note.

CAR-T therapies are personalized, built from the immune cells of each individual patient. Manufacturing is complex and can be challenging to get right every time. Bristol Myers said it has a manufacturing success rate of 94% providing Abecma in the commercial setting, while J&J said it aims to double production capacity this year.

In addition to granting Carvykti an expanded approval, the FDA also cleared more favorably manufacturing specifications, according to Shi.

The Food and Drug Administration on Aug. 2 approved a new type of cellular medicine, clearing a therapy developed by the biotechnology company Adaptimmune for a rare soft tissue cancer called synovial sarcoma.

The agency granted Adaptimmune’s therapy, formerly known as afami-cel and to be sold as Tecelra, an accelerated approval for use in some people with metastatic synovial sarcoma who previously received chemotherapy. Those people must have certain immune signatures and tumors expressing a protein, MAGE-A4, that Tecelra is designed to target.

The FDA based its decision on Tecelra’s ability to spur tumor responses in about 43% of people who received it in a clinical trial, with responses lasting a median of about 6 months, according to the therapy’s new labeling. Adaptimmune has to confirm those benefits in an ongoing study to maintain the approval. The company expects to submit those results next year, executives said on an Aug. 2 conference call with analysts.

Adaptimmune is launching Tecelra — a one-time treatment — at a list price of $727,000, the most expensive per-dose cost of any cellular medicine for cancer in the U.S. The figure was “based on the clinical value that it brings to patients” with a “rare type of tumor and with a very high unmet need,” said Cintia Piccina, Adaptimmune’s chief commercial officer, during the call.

The American Cancer Society estimates 13,590 people will be diagnosed with soft tissue cancers in the U.S. this year, making them among the rarest types of tumors. Some estimates hold that about 5% to 10% of those tumors are synovial sarcomas, which are aggressive and typically affect men in their 30s or younger. Treatment options are limited, and median five-year survival rates for people with metastatic disease are about 20%, according to Adaptimmune.

“The approval of this state-of-the-art immunotherapy technology provides a critical new option for a patient population in need and demonstrates the FDA’s dedication to the advancement of beneficial cancer treatments,” said Peter Marks, the head of the FDA office that evaluates gene and cell therapies, in an Aug. 2 statement.

Adaptimmune hasn’t yet proven its treatment can extend lives. An exploratory analysis from the company showed that, so far in testing, responding patients had a two-year survival probability of about 70%.

The approval of Tecelra marks another step forward for the field of cell therapy. Prior to Thursday, the FDA had OK’d six CAR-T therapies for cancer and, earlier this year, issued the first clearance for a different kind of immune cell treatment.

Tecelra is what’s known as a TCR cell therapy. Like CAR-T therapies, these treatments give a patient’s immune cells special receptors with the ability to recognize a protein flag — in Tecelra’s case, MAGE-A4 — that tumors possess.

TCRs are designed to find intracellular targets, not just those on a cell’s surface. In theory, that feature should help them reach the solid tumors CAR-Ts have difficulty treating. Tecelra’s approval is evidence of that, marking the first time an engineered cell therapy has been cleared by the FDA for a solid tumor. (Iovance Biotherapeutics’ recently approved melanoma therapy Amtagvi doesn’t rely on the same genetic engineering as Tecelra.)

Tecelra is also the first new treatment for synovial sarcoma in more than a decade, according to Adaptimmune. “This is a watershed day,” said company CEO Adrian Rawcliffe, on the conference call.

The approval comes after a long and difficult journey for Adaptimmune. Formed in 2008, the company lost multiple partnerships, laid off staff and restructured its pipeline over the years. Even after the approval, shares were trading Friday at just over $1 apiece, a fraction of their initial offering price in 2015 and indicative of investor skepticism about Tecelra’s sales potential.

Analysts at Mizuho Securities this year lowered peak annual sales projections for the drug to $174 million amid expectations of “conservative uptake.” As with other cell therapies, Tecelra will only be available at “authorized treatment centers” equipped to administer it. Adaptimmune expects six to 10 will be up and running this year and 30 within two years.

The company anticipates its first commercial sales will come in the fourth quarter, and for those numbers to be “modest” before increasing in 2025, Rawcliffe said.

Adaptimmune views Tecelra as the first step in a larger business in soft tissue cancers. A second therapy, lete-cel, could be submitted to regulators next year for two types of sarcomas. Adaptimmune estimates the two therapies combined could generate $400 million in peak yearly sales in the U.S. and climb higher if cleared in other geographies and sarcomas, as well as earlier treatment lines.

“There’s a lot of potential, over time, to expand use,” Rawcliffe said.

Developing a new drug is a long, expensive process that comes with a high risk of failure, often because would-be medicines are unsafe or ineffective.

For companies specializing in cell or gene therapies, an equally pressing concern is figuring out how to reliably make their products. Unlike small molecule or antibody drugs, genetic medicines typically involve a variety of specialized parts woven together through a complex process.

"Ex vivo," or outside-the-body, treatments can involve a multi-week process for collecting, multiplying and modifying a patient's cells in a laboratory. Even the simpler "in vivo" therapies have multiple pieces, including engineered viruses and synthetic genetic material, that are challenging to produce at scale.

The approvals of a dozen cell- and gene-based medicines for cancer and inherited diseases in recent years has given young drugmakers a path to pursue. But most of those approvals were won by large pharmaceutical or biotechnology companies that invested heavily in manufacturing. Startups, by contrast, don't yet have that luxury.

Still, cell and gene therapy research is booming. More than 2,200 clinical trials testing these types of treatments were ongoing globally as of 2022, according to the Alliance for Regenerative Medicine. The surge has often outstripped the capacity of large contract manufacturers, leaving startups facing waitlists that can stretch one to two years.

A growing group of new manufacturers aim to help. Since 2017, at least half a dozen companies have launched with plans to ease the "bottlenecks" slowing down aspiring cell and gene therapy developers. Many have been started by veterans of the young field and gotten the backing of top venture firms. Here's what they aim to accomplish and how their work is progressing:

What are the main bottlenecks in cell and gene therapy manufacturing?

Cell and gene therapies involve materials that aren't used in many of the other products the pharma industry is well-versed in producing.

Scientists design synthetic genetic material to deliver into patients, either via their own cells, benign viruses known as vectors or specially made bubbles of fat. Constructing these treatments is tricky even in a research setting, where small amounts of such material might be required for early experiments. But it's much harder for companies running clinical trials, or preparing for mass production.

Manufacturing delays can wreak havoc on young companies, causing them to miss milestones that could endanger future funding. Established gene therapy biotechs like UniQure or BioMarin Pharmaceuticals have spent years and millions of dollars to build their own plants. But startups and academic labs — where a number of the approved cell and gene therapies originated — can’t afford that.

“Academics have truly cutting-edge research, and I have been blown away by some of the creative ideas, novel modalities and breakthrough innovations that came about,” said Ran Zheng, the CEO of Landmark Bio, a Massachusetts-based company that caters to cell and gene therapy developers. “But that information needs to be translated into therapeutics, and this is the biggest, and probably the first, hurdle [startups] have to overcome.”

Turning to contract manufacturers like Thermo Fisher and Catalent can be a solution, but brings problems of its own. Transferring technology from a small lab to a larger organization can be arduous and require troubleshooting for glitches that arise in the process.

Big CDMOs may also prioritize more lucrative work with larger biotech and pharmaceutical firms. And they're struggling to meet the surging demand for cell and gene therapy manufacturing tools themselves.

Building up capabilities internally can be costly for startups. Viral vectors, for instance, are expensive to make and handle.

“You often see companies trying to own their own manufacturing and unfortunately, in this environment, if the product’s not successful, that's a heavy capital and operating expense to carry,” said Mike Paglia, a senior executive with ElevateBio, a richly funded startup that helps manufacture cell and gene therapies.

How are these startups trying to change that?

Rather than compete directly with larger CDMOs, some manufacturing startups aim to provide a more cost-efficient path for companies to develop in-house production capabilities. To appeal to younger biotechs that may need them, they are building relationships earlier and providing more services to attract first-time founders and small teams.

Many of these conversations take place long before an application to begin human testing, so these smaller manufacturers work to teach startups about raw material control strategies and set realistic timelines to gather early clinical data.

“Traditional CDMOs are like a kitchen, you'll give them a recipe and they make an entree,” said Zheng, who previously worked in manufacturing and operations at Orchard Therapeutics and Amgen. “That’s all they do. We're not like a kitchen where you just simply state the recipe. We actually ask our clients what ideas they have and we develop the recipe with them.”

Some clients start from near the beginning, working with these newer manufacturers from the moment they identify a lead candidate.

ElevateBio and Landmark Bio both help startups with laboratory studies to ensure that, down the line, they’re familiar with how to transfer their drugmaking technology to the companies that might eventually produce their therapies.

Paglia, who previously worked at Bluebird bio, said the biggest hurdle for him and his former colleagues was transferring their technology to contract manufacturers.

“Whether it was manufacturing our lentiviral vectors or cell therapy products, it took tremendous amounts of oversight to get those processes right because of the infancy of the industry,” he said.

Still, outsourcing to a dedicated manufacturer can save biotechs millions of dollars in the long term, Paglia said, allowing them to put that money toward additional clinical studies. That has meant steady demand for CDMOs, and created business for new startups trying to help.

Manufacturing startups have also attracted academics and nonprofits that struggled to get time with larger CDMOs. Landmark has worked with researchers who have received National Institutes of Health grants, for example.

Ultimately, improving manufacturing might give companies an opportunity to rethink how they price cell and gene therapies, which are some of the costliest medicines to make. The few companies that have reached market have noted these high costs in setting price tags that range from hundreds of thousands to millions of dollars.

Who are the startups in the space?

At least six biotech startups have launched since 2017 to address shortfalls in cell and gene therapy manufacturing.

The most richly funded, ElevateBio, has raised about $1.3 billion since it began working with drugmakers. It’s also spun out its own biotech startup with Boston Children’s Hospital to develop more convenient alternatives to current cancer cell therapies.

More recently, Ascend Cell & Gene Therapies in the U.K. emerged from stealth armed with $130 million in funding and led by industry veterans. It’s focused on adeno-associated viruses, a heavily used type of viral vector, and has acquired some of its capacity and technology from the struggling Freeline Therapeutics.

“AAV manufacturing is complex and needs teams that show real expertise and ownership,” said one of Ascend’s founding investors, Tim Funnell of Monograph Capital, in a statement on the company’s launch. “This led many advanced modality biotech developers to build their own internal CMC capabilities. However, these companies are now finding it difficult to sustain and fully utilize their facilities.”

There are smaller ventures, too. A pair of University of Pennsylvania researchers who worked on the cell therapy Kymriah and the gene therapies Zolgensma and Luxturna launched VintaBio last April. Months before in January 2023, biotech startup creator Versant Ventures debuted Vector BioMed to help supply startups with the "lentiviral" vectors often used in ex vivo treatments.