Cell therapy

The clue came, as they often do, from an unexpected source. A year and a half 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 nearly a dozen 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.

Cabaletta has said it will share results from patients with lupus or myositis in the first half of 2024. ImmPACT and Sana could also report initial data in 2024.

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.”

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.

Sponsored content

By Fortrea

The number of non-oncologic CAR T-cell therapy trials has rapidly increased since the first chimeric antigen receptor (CAR) T-cell therapy, KYMRIAH®, was approved by the U.S. FDA for the treatment of acute lymphoblastic leukemia.^[i] As of January 2024, Citeline’s Trialtrove® data listed 66 CAR cell therapy non-oncology trials, with 55 in Phase I/II, predominantly focusing on autoimmune and inflammation indications.

Treatment approaches vary, but CD19 is the primary target for non-oncologic CAR therapies in Citeline’s Trialtrove® data. A February 2024 publication reported a follow-up of patients with systemic lupus erythematosus (SLE), idiopathic inflammatory myositis and systemic sclerosis treated with CD19 CAR T-cell transfer, finding that the treatments were “feasible, safe, and efficacious”^[ii] urging further clinical research.

This article provides operational considerations for sponsors developing CAR T-cell therapies in non-oncologic indications spanning site identification and support, patient education and logistics.

Operational challenges in non-oncologic CAR-based trials

While transitioning a therapeutic technology initially developed for oncologic indications into autoimmune indications has been previously demonstrated, for example, with monoclonal antibodies, CAR-T treatments are more complex in terms of administration, adverse event management and long-term follow-up (LTFU). At a high level, the most significant challenges include:

Finding the optimal site: Depending on the indication, an institution or site may have experience with cell and gene therapies but its investigator for the indication may not yet have specific experience with CAR T-cell therapies. In addition, institutions may have limited capacity or underestimate a trial’s complexity and the long-term commitment required. The ideal institution or site should have cross-functional expertise, such as an indication-specific principal investigator (PI), a team experienced with CAR-based cell therapies, adequate support staff and hematology/oncology specialists that understand safety profiles and can also manage lymphodepletion, chemotherapy/immunotherapy any associated toxicities following treatment administration.  

Promoting patient access and education: Sites need access to indication-specific and age-specific populations, and ideally the ability to accept referred and international patients if studying a rare disease. From the perspective of educating families and enabling patient advocacy support in these trials, understanding the patient journey and their acceptance of the trial protocol is crucial for recruitment and retention efforts, especially as the risk/benefit profile may vary from treating life-threatening cancer.

Handling complex logistics: CAR-T trials often experience a slow start or limited progress as they respond to manufacturing limitations as well as frequent protocol amendments. Logistics supply chain challenges can also arise, depending on the location of the pharmacy within the institution as well as the location of a manufacturing or distribution site.

Increasing operational efficiencies

Reflecting on lessons learned in oncology CAR-T cell studies, the following tactics can help drug development sponsors and their partner CROs advance more efficient and effective studies in non-oncologic CAR T-cell therapy trials.

Forming a multidisciplinary collaboration: In partnership with the sponsor and the CRO, sites could form a “Cell Therapy Board” to actively bridge the gap between current CAR-T cell therapy experts and any “newcomers.”This collaboration helps build a strong rapport early in the process, initiates critical protocol feedback, promotes continuous engagement and strengthens focus on the patients.

Starting slow to finish fast: Investing time upfront in planning and mapping out processes and procedures helps identify potential roadblocks, like regulatory and institutional policies, contractual issues across hospital departments and operational logistics of the cell therapy product. Anticipating these bottlenecks allows sponsors and CROs to provide timely solutions and support new challenges over time.

Building a network of sites: Not all enlisted sites may initially have specific cell and gene therapy experience. Employing a “hub and spoke model” allows a highly specialized center to handle most complex tasks and procedures, such as selecting suitable patients, treatment planning and execution and overseeing the prevention and management of treatment-related toxic effects. The more standard and less complex study procedures can be administered at secondary sites, closer to the patient population, promoting a patient-centric approach.

As clinical research of CAR-T cell therapies expands beyond oncology, sponsors and CROs should leverage insights from oncology trials to inform the setup of non-oncology trials.

To learn more about how Fortrea can help advance CAR T-cell studies in non-oncology indications, visit us online.

Sales of Johnson & Johnson’s multiple myeloma medicine Tecvayli more than doubled in the first quarter versus the same period last year, boosting the pharmaceutical company’s oncology business while its cell therapy for the blood cancer, Carvykti, underperformed.

The first quarter figures released April 16 by J&J were the first time it has broken out sales of Tecvayli, which was approved in the U.S. in late 2022. The dual-targeting antibody drug brought in $133 million between January and March, above analysts’ estimates.

Tecvayli’s growth contrasted with Carvykti, sales of which were flat in the first quarter compared to the final three months of last year. J&J, which has been working to improve how it produces the complex cell treatment, cited the timing of orders as the main reason for Carvykti’s slower-than-expected sales.

J&J has put multiple myeloma drug development at the center of its pharma business strategy, setting a target of $25 billion in sales by 2030 and at least 50% share of patient treatment.

For much of the past decade, its oncology business has been led by Darzalex, an antibody that’s become a backbone therapy for multiple myeloma. Sales have continued to grow, rising 19% year over year in the first quarter to about $2.7 billion.

Tecvayli and Carvykti, along with a newer medicine called Talvey, are meant to build on Darzalex by offering new ways to target the blood cancer, as well as opportunities for treatment combinations. Tecvayli and Talvey are both bispecific antibodies that bind to different myeloma cell proteins, while Carvykti is a personalized cell therapy.

Manufacturing the latter is a complicated undertaking and for months, J&J has been working to improve how reliably it can make Carvykti. The company claimed it’s doubled capacity since last year, adding new production facilities and bringing on contract suppliers.

The increased supply will be needed if demand grows as J&J expects following the Food and Drug Administration’s recent decision to approve earlier Carvykti treatment. The therapy can now be used after only one prior drug regimen for people with relapsed or refractory multiple myeloma, compared to the previous indication for use after four lines of therapy.

While Carvykti sales were flat in the first quarter, Jennifer Taubert, J&J’s head of innovative medicine, cited the “timing of orders and when they were actually delivered and billed.”

“Nothing [...] to really see there,” she added, on a Tuesday call with analysts. “We do anticipate continued growth for this asset, particularly in the second half versus the first half.”

J&J faces competition from Bristol Myers Squibb, which has a rival cell therapy called Abecma, as well as from other companies like Pfizer that have developed bispecific antibodies.

Taubert noted Tecvayli has seen strong adoption in the U.S., as well as in countries like Germany and France, and said it was performing well versus the competition.

Overall, J&J’s cancer drug sales totaled $4.8 billion in the first quarter, up 17% year over year and accounting for some 35% of the company’s pharma business.

AstraZeneca’s plan to reach $80 billion in sales by 2030 relies heavily on a slate of roughly one dozen cancer drugs it expects will become blockbuster sellers at their peak, according to a presentation to investors that executives outlined in late May.

One of the drugs, the lung cancer treatment Tagrisso, has already exceeded $5 billion in annual sales and another, Imfinzi, is approaching that mark. But four use technologies AstraZeneca hasn’t previously employed and will either take on or trail products from rival drugmakers.

Broadly, AstraZeneca aims to develop drugs that supplant toxic chemotherapies as well as immunotherapies known as checkpoint inhibitors. Its large pipeline of antibody-drug conjugates, which add tumor cell-targeting to chemical toxins, will play a large role in achieving the former goal.

AstraZeneca has reinvented itself over the past decade, shifting from its prior focus on mental health, respiratory and cholesterol drugs to emphasize oncology. There, its strength has been in targeted therapies and in antibody-drug conjugates, as it has come late to fields like immunotherapy and radiopharmaceuticals. Imfinzi, the company’s flagship immunotherapy, arrived fifth to market in the U.S. and last year earned sales that were one-fifth of Merck & Co.’s Keytruda, the leader in the space.

AstraZeneca plans to change that picture. In immunotherapy, it’s developing bispecific antibodies that target the PD-1 pathway. One, called rilvegostomig, binds to another immunity-modulating pathway called TIGIT, which has proven a difficult target even in combination with PD-1 drugs.

Another, known as volrustomig, binds to PD-1 and a target called CTLA-4, essentially duplicating a two-drug combination of Imfinzi with another immunotherapy called Imjudo.

AstraZeneca also plans to make a mark in cell therapy, which has so far been led by Novartis, Gilead and Bristol Myers Squibb, as well as biotechnology companies like Legend Biotech and Bluebird bio. Leading AstraZeneca’s efforts is a dual-acting therapy that hits a protein active on multiple myeloma cells, along with CD19. The company claims it can make that drug, which would compete with Legend and J&J’s Carvykti and Bristol Myers’ Abecma, in a few days, rather than the weeks current CAR-T therapies take to produce.

Outside of immunotherapy, AstraZeneca is advancing a new type of hormone therapy for breast cancer that it’s testing in post-surgical and inoperable settings, paired with types of targeted therapies in some cases. In breast cancer, it is also studying a so-called PARP inhibitor known as saruparib, which could potentially replace its $2 billion-a-year drug Lynparza.

Antibody-drug conjugates, which pair the tumor-targeting of antibodies with the cell-killing power of chemotherapies, will continue to play a large role in AstraZeneca’s cancer drug plans, too.

The company already markets one, the breast cancer drug Enhertu, and has another now before regulators, called datopotamab deruxtecan and also for breast cancer. Peter Welford, an analyst at Jefferies, forecasts that latter drug will earn nearly $6 billion in sales in 2030.

AstraZeneca has six other clinical-stage ADCs. Combined, its ADC assets could be used in 17 different types of cancer.

Beyond 2030, the drugmaker expects to add radiopharmaceuticals, or hybrid radiation-emitting drugs, to its arsenal. AstraZeneca paid $2.4 billion in March to acquire Fusion Pharmaceuticals, a developer of such products that has a prostate cancer drug in Phase 2.

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.

What’s the status of their work?

With demand for more CDMOs at an all-time high, these startups are partnering with drugmakers straight out of the gate. Though many rely on capital infusions from venture firms, they also can generate cash from their work early on, bringing returns to investors well before a typical biotech might.

Landmark Bio had its first customer “even before we put a sign on the door,” Zheng said in October. In early June, it announced a partnership with InnDura, a new biotech company focused on “natural killer” cell research.

ElevateBio, having been around for some years, boasts a larger client list, noting in a May fundraising announcement that it added more than 15 new biopharmaceutical partners over the past year. Its subsidiary Life Edit Therapeutics is collaborating with large drugmakers like Novo Nordisk and Moderna.

VintaBio has a 22,500-square-foot facility in Philadelphia that’s now open for business, while Vector BioMed is working out of Gaithersburg, Maryland.

Shape Therapeutics is somewhat different, as it’s working on its own research, too. But it has also hinted at playing a manufacturing role, developing a new kind of cell line for producing adeno-associated viruses and indicating plans to build a factory where other companies can make their therapies.

Bristol Myers Squibb is turning to a manufacturing startup to help produce cancer cell therapies faster, announcing April 22 a partnership with the South San Francisco, California-based Cellares.

The deal, which reserves Cellares’ production capacity for Bristol Myers’ use, is worth up to $380 million in upfront and milestone payments. Cellares will handle technology transfer of certain Bristol Myers cell therapies to its automated manufacturing platform, dubbed the Cell Shuttle.

Bristol Myers currently sells two so-called CAR-T cell therapies, Breyanzi for lymphoma and Abecma for multiple myeloma, and has several others in development. In a statement, Lynelle Hoch, head of the pharmaceutical company’s cell therapy unit, said the Cellares deal would help it meet demand for CAR-T therapies “now and in the future.”

Made from patients’ own immune cells, CAR-T therapies are personalized treatments. Their production is precisely choreographed, as frozen cells are brought to manufacturing hubs where they are engineered and expanded into a cancer-seeking drug product. It’s laborious, time-consuming and costly.

Currently, CAR-T manufacturers need somewhere between two to three weeks to turn around a therapy for use in treating a patient. Companies like Cellares aim to improve on that standard through a variety of methods, among them automating production and moving manufacturing closer to treatment sites.

Cellares’ chief solution is along the lines of the former. The startup, which has raised more than $350 million from a group of investors that includes Bristol Myers, pitches its Cell Shuttle platform as both cheaper and more efficient than existing processes.

Resembling a sort of giant MRI machine, the Cell Shuttle is a miniature factory, housing all the technologies needed to make a CAR-T drug dose. Cellares claims it can reduce manufacturing failure rates, require drastically less labor and shave 50% off of average production costs.

The startup will dedicate multiple Cell Shuttles and associated quality control systems for Bristol Myers under the partnership. The shuttles will be housed in facilities located in the U.S., Europe and Japan, the companies said. Cellares’ current commercial-scale facility is in New Jersey.

In an email, a spokesperson for Cellares also noted the deal “strengthens Cellares’ position as a U.S. manufacturer” at a time when Congress is considering legislation that could restrict U.S. drugmakers from working with Chinese biotechnology companies like WuXi Apptec.

“This agreement with Bristol Myers Squibb is aligned with our strategy of establishing a global network of high-throughput, automated Smart Factories to meet the growing and worldwide demand for cell therapies,” said Fabian Gerlinghaus, Cellares’ CEO and co-founder, in a statement.

The Food and Drug Administration has cleared a new kind of cell therapy, granting Feb. 20 an accelerated approval to Iovance Biotherapeutics’ Amtagvi for people with an advanced form of skin cancer.

Amtagvi is the first marketed cellular medicine made by engineering immune cells known as tumor-infiltrating lymphocytes, or TILs. It’s for people whose melanoma can’t be surgically removed or has spread to other parts of the body, and is meant to be used after other medicines.

The FDA’s OK was based on data showing Amtagvi shrank tumors in testing, a benefit that must be confirmed in an ongoing Phase 3 trial. Iovance set the drug’s list price at about $515,000, the highest of any cell-based medicine for cancer in the U.S. Its prescribing information includes warnings for the risk of low blood cell counts, severe infections or kidney problems.

Amtagvi’s approval has been a long time coming for Iovance.

TIL therapy originated from research at the National Institutes of Health in the 1980s. It took decades to fine-tune, and Iovance had to overcome multiple regulatory delays bringing the therapy, formerly known as lifileucel, to market.

Its clearance is the “culmination of scientific and clinical research efforts,” said Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, in a statement.

An estimated 8,000 people die from melanoma each year, according to Iovance. Until now, there haven’t been drugs available for people whose cancers progress after a commonly used immunotherapy or targeted cancer medication.

Iovance must now prove it can manufacture and deliver a cell therapy, a complicated task that has challenged even large drugmakers like Gilead Sciences, Novartis and Bristol Myers Squibb, which sell a different kind of cell therapy for a range of blood cancers.

Amtagvi is derived from a tumor sample that’s surgically removed. Select immune cells that have “infiltrated” the tumor are isolated, grown and filtered via a weekslong manufacturing process. It currently takes Iovance 34 days from the time a sample is received to make and ship back each personalized TIL therapy — longer than with the CAR-T cell therapies from Gilead, Novartis and Bristol Myers.

“We think we can improve on it over time,” said CEO Frederick Vogt, on a conference call with analysts.

Executives said 30 treatment centers will be active initially, climbing to over 50 within 90 days of the FDA’s original approval decision date of Feb. 24.

Still, Stifel analyst Benjamin Burnett noted there’s some questions among experts as to how many of those centers are currently capable of administering Amtagvi. There’s also debate among investors about demand and the complex logistics involved.

“Cell therapy launches have been clunky,” Burnett wrote in a research note.

For its part, the company anticipates “strong market access and patient reimbursement” given early response from payers, Jim Ziegler, the company’s executive vice president of commercial, said. The majority of patients are on commercial insurance, he said.

“We expect a bolus of patients coming through as the product launches and we start to see the manufacturing flow,” said Vogt.

Iovance wouldn’t detail how much revenue it expects to earn. But the company’s current manufacturing capacity and pricing imply Amtagvi could generate $185 million in its first three quarters on the market, wrote Jefferies analyst Michael Yee.

“Consensus numbers look doable,” Yee wrote in a client note, adding that Iovance “would make a nice tuck-in for big pharma, who could leverage this even better.”