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 year 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 filed for an initial public offering earlier this month. 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.”

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 in April. Months before in January, 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.

Sponsored content

By Resilience

The cell therapy landscape is evolving at an energizing speed - with over 1,000 ongoing clinical trials and several recent commercial approvals, the momentum in the industry is palpable. That excitement is contrasted by a halting reality: the COGS for these advanced therapies will continue to shape their adoption and accessibility to patients in need.

Academic investigators developing these therapies are the backbone of the innovative research engine in the cell therapy industry. In many cases, the manufacturing processes used in academia do not take scalability and COGS into account. Once a therapy shows clinical promise and is spun out or acquired by a biotech or pharmaceutical company, there is a drive to progress quickly through later clinical stages, making it difficult to stop and invest the time and funds needed to improve processes and COGS. Unfortunately, this has led to some therapies failing to garner widespread adoption, being too expensive and difficult to manufacture. To alleviate this cycle, CDMOs can partner with academic centers to help implement best-in-class manufacturing and analytical methods as early as possible.

Are CDMOS Incentivized to Help Reduce COGS?

As more indications are becoming treatable with cell therapies, COGS will increasingly become a bottleneck. CDMOs can play a pivotal role in shaping the cost dynamics of these therapies and impacting their commercial success. While there are many drivers that can impact COGS, which can vary from one advanced therapy to the next, the lengthier and more complex the manufacturing process is, the higher the COGS and the more money per batch CDMOs make. This structure does not incentivize CDMOs to implement more efficient manufacturing processes.

CDMOs and therapeutic companies can jointly realize efficiency and mutual benefits in several ways, the key is creating genuine long-term incentives by rewarding the CDMO for the commercial success of the therapy. Aligning incentives can result in a better alignment between the therapeutics company and the manufacturer. Using novel business structures to serve patients better and foster a synergistic relationship between therapy developers and biomanufacturing service providers will accelerate clinical activities and improve the chances of clinical and commercial success.

Major COGS Drivers for Autologous & Allogeneic Cell Therapies

Both allogeneic and autologous cell therapies have significant technological challenges in manufacturing and quality, which is an opportunity to facilitate a true and considerable reduction of COGS. There is a lack of large-scale fit-for-purpose downstream solutions for allogeneic therapies and a lack of closed, automated, and space-efficient manufacturing platforms for autologous therapies. Another major area that drives COGS, as well as vein-to-vein turnaround time, is QC release. Working with a CDMO with deep expertise in manufacturing cell therapies can be advantageous in these areas. They understand, track, (or even develop) solutions for COGS drivers and can implement the latest and most innovative technologies to maximize the chances of the therapy succeeding in the clinic and commercially. Resilience’s development of a next-generation QC platform, designed as an all-in-one automated system that consolidates all release testing into one workflow, strives to reduce release time of cell therapy products by 60%-90% and reduce costs of QC by 50%-60%. The use of existing QC methods does not support release timelines, throughput volume and COGS reduction needed in the industry. By automating QC methods and shifting to more rapid and less labor-intensive processes, we can enable a reduction in COGS and enhanced scalability.

In addition, there are efforts to reduce the duration of cell culture time needed for autologous therapies. Several therapeutic companies have developed 1–3-day CAR-T processes to replace existing 7–12-day processes. Resilience is at the forefront of this effort, developing a robust 3-day process that not only reduces manufacturing time, therefore reducing COGS and increasing throughput, but also improving the phenotype of the cell therapy product. 

While the COGS issue encompasses many elements, the key drivers are the length, complexity, and the manual nature of many processes and quality control methods. As manufacturing technologies have not kept up with the pace of therapeutic innovation, CDMOs have a responsibility to fill these gaps in innovation with their expertise and to strive towards COGS reduction and faster vein-to-vein time. These types of advances will make these therapies accessible to more patients, as well as allow cell therapies for larger indications (e.g., solid tumors, autoimmune disorders, infectious diseases, etc.) and non-life-threatening indications (e.g., diabetes, orthopedic) to become a reality.

Advisers to the Food and Drug Administration have endorsed the use of two cellular medicines for multiple myeloma earlier in a patient’s disease, overlooking safety concerns raised by agency reviewers.

The advisory committee on March 15 voted unanimously, 11-0, that the benefits of Johnson & Johnson and Legend Biotech’s Carvykti outweighed the risks when administered to patients as early as after their first relapse. They cast a narrower, but similarly positive vote, 8-3, for Bristol Myers Squibb’s Abecma. 

The impact ot treatment “is significant and offers our patients a chance of significant time off therapy with associated quality of life improvement,” said Christopher Lieu, an associate medical professor at the University of Colorado, who voted in favor of Abecma and Carvykti. “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.” 

The votes increase the likelihood that use of both therapies, which are currently available to myeloma patients following at least three lines of treatment, will be expanded in the U.S. European regulators have already endorsed such a decision. The FDA doesn’t always follow the advice of its advisory committees, but usually does. 

The panel threw their support behind Carvykti and Abecma based on studies showing they helped people with the blood cancer live longer without their disease progressing when compared to standard drug regimens.

In doing so, panelists waved off concerns flagged by FDA reviewers in briefing documents posted earlier this week. In those documents, the agency cited an increased risk of early death in patients who received Carvykti or Abecma. Specifically, FDA statisticians found a higher risk of death in patients who’d received Carvykti in the first 11 months of the study supporting its application. For Abecma, that elevated risk lasted 15 months. 

While acknowledging the FDA’s findings, some experts countered that patients would likely choose treatment anyway given the length of the remissions observed in testing of Carvykti and Abecma.

“The question is whether or not the patients are willing to undertake the risk,” Lieu said following the positive Carvykti vote. “The answer will likely be ‘yes’ for patients who may want just a chance at a longer time off treatment.”

The FDA, for its part, noted that the therapies haven’t yet clearly shown they can extend lives. “It may be when the data are more mature, but it's not there yet,” said Robert Sokolic, the head of the agency branch that reviews hematology drugs.

Agency staff also claimed that the early deaths in testing weaken the overall results and purported long-term benefits of treatment. The known side effects of CAR-T therapy, as well as the conditioning regimens used to prepare patients for treatment, may have elevated patients’ death rates in testing, making the benefits of therapy less clear.  

“All these risks should be considered integral to the benefit-risk assessment of CAR-T cell therapy,” Helkha Peredo-Pinto, an FDA clinical reviewer, told committee members.

However, Jordan Schecter, J&J’s vice president of R&D, argued that the picture would look different outside the confines of a clinical trial. Some of the early deaths in testing could have been averted if physicians had been able to give patients the best possible “bridging” therapy while they awaited CAR-T treatment. The complex therapies take weeks to manufacture, during which time patients’ disease can progress.  

The increased risk of early deaths in the trials “need to be explained,” said Brian Durie, the chairman of the International Myeloma Foundation. But “the key point for me is that it was occurring in this preparatory period,” and was “not associated with the CAR-T therapy itself.”

Jorge Nieva, an associate medical professor at University of Southern California, added that other cancer therapies, such as stem cell transplants, have a “front-loaded” risk of death but better long-term outcomes than alternative treatments.

But Nieva, along with other panel members, agreed that the issues surrounding the use of bridging therapy in testing shouldn’t be as much of a problem in clinical practice. Physicians won’t be burdened by clinical trial rules that delay CAR-T treatment and restrict bridging therapies, he said.

“A reason for some of the problems here is, in a way, an artifact of the clinical trial process,” he said. “In the real world, where collection and manufacturing could occur early in the course of disease, that may be less of an issue for patients.”

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.”

Cargo Therapeutics in a November initial public offering raised $281 million to fund the biotechnology startup’s plans for developing better cancer drugs.

The San Mateo, California-based company priced 18.75 million shares at $15 apiece, on the low end of its proposed price range. Its IPO was the fourth largest in 2023 for a biotech, according to BioPharma Dive data.

Cargo’s focus is on CAR-T therapies, a type of cellular treatment for several kinds of blood cancers. While some patients benefit greatly from CAR-T therapy — companies like Gilead have recently received expanded clearances for their CAR-T drugs based on strong data — not all do. Others relapse months after treatment.

Cargo’s lead program, dubbed CRG-022, is in Phase 2 clinical testing for patients with large B-cell lymphoma that is relapsed or refractory to existing CAR-T therapies. While CAR-T therapies approved by the Food and Drug Administration for lymphoma target a protein called CD19, CRG-022 is aimed at a different protein, CD22. Cargo claims its treatment can treat cancers that don't respond to or have evaded CD19-directed treatment.

CRG-022 is also being tested in patients who have not had other CAR-T therapies as well as children with B-cell acute lymphoblastic leukemia. A second program, CRG-023, is in preclinical studies for B-cell malignancies.

Cargo announced it had raised a $200 million Series A round in March, backed by notable biotech investors such as Samsara BioCapital and Third Rock Ventures.

“Given Cargo’s progress to date and its experienced leadership team, Cargo is well-positioned to be first-to-market with an autologous CD22 CAR T-cell therapy,” Reid Huber, a partner at Third Rock Ventures, said at the time.

That projection hinges on the biotech’s ability to fund its clinical trial plans. In a securities filing ahead of its public offering, Cargo wrote that its cash on hand and proceeds from two tranches of stock issued in March and October “will not be sufficient to fund our operations for at least one year from the issuance date of our financial statements.”

However, the proceeds from the IPO should stretch its financial runway into 2025, the company said in the document.

Cargo was one of seven cancer-focused drugmakers — and the 19th biotech overall — to price a new stock offering in 2023, according to BioPharma Dive data.

At $281M, Cargo’s offering was also the second-largest by a cancer drugmaker in 2023, behind RayzeBio’s $311 million IPO in September. It matched the profile of biotechs that successfully pulled off IPOs last year, when investors looking for surer bets gravitated toward companies with clinical data.

In 2011, cancer cell therapy was closer to science project than treatment. 

Immunologist Carl June and his colleagues at the University of Pennsylvania were struggling to raise money for a small study of a cell therapy for leukemia. The trial “was an academic exercise,” said June. “We had no idea it would turn into a commercially viable product.” 

The treatment June was working on, now sold as Kymriah, became the first CAR-T cancer therapy to reach market, establishing cell therapy as a new class of medicines. Other, similar treatments have followed since and are used to treat leukemia, lymphoma and multiple myeloma. When they work, they can produce durable remissions. 

Yet, despite a decade of rapid progress since June’s 2011 study, CAR-T therapy’s reach remains limited. It hasn’t been used effectively for non-malignant diseases and, even in oncology, its success is confined to blood cancers.

Many companies are working to overcome CAR-T’s shortcomings and broaden its potential applications. One strategy involves turning CAR-T from a complex process performed outside the body into a simpler infusion. This inside-the-body, or “in vivo,” approach could make cell therapy more accessible. It also may open up other conditions for CAR-T treatment. 

At least five startups have formed in recent years to develop in vivo cell therapy. June co-founded one of them, Capstan Therapeutics, and the rest have drawn interest from top-tier investors or large pharmaceutical companies. Here’s where things stand: 

What is in vivo cell therapy and how does it work? 

Constructing a CAR-T therapy is delicate, laborious work. Doctors must first draw out a patient’s white blood cells, which are then frozen and shipped to a laboratory. There, scientists alter T cells by adding a gene for a new receptor — called a chimeric antigen receptor, or CAR — that helps them grab proteins on the surface of cancerous cells. These souped-up T cells are multiplied many times over, frozen and — about two to three weeks after the whole process began — reinfused back into the patient. 

With Kymriah, for example, T cells are modified to lock onto a protein called CD19 that’s expressed on cancerous B cells in leukemia and lymphoma. Multiple myeloma cell therapies like Bristol Myers Squibb’s Abecma, by comparison, consist of T cell hunters seeking a protein called BCMA. 

Once these engineered CAR-T cells are infused, they search for and destroy cancer cells expressing their target proteins, sometimes driving an immune response so strong it can be life-threatening.  

As the bulk of this work takes place in a lab, CAR-T is considered an “ex vivo,” or outside-the-body, procedure. With in vivo cell therapy, companies aim to modify immune cells inside the body, with the help of technologies like gene editing and messenger RNA. 

June’s startup, Capstan, is using mRNA technology similar to that involved in COVID-19 vaccines to teach T cells to recognize diseased cells. Its founders showed that mRNA stuffed into fatty spheres known as lipid nanoparticles are taken up by heart cells in mice, where they were translated into new surface proteins and helped repair damaged tissue. Umoja Biopharma, meanwhile, is using lentiviruses to deliver genes designed to help the body make its own CAR-T cells. 

Other startups are also turning to in vivo cell engineering. Ensoma is carving out the viral genome of an adenovirus and using it to carry gene editing instructions into the body. Vector BioPharma, meanwhile, uses virus-like particles to transfer genetic material into the body. Both approaches could be used to treat inherited diseases as well. 

These methods come with risks. Synthetic mRNA, for example, can trigger an immune response that, while helpful for a vaccine, could be harmful when used as treatment. Adenoviruses have a checkered past, having been the source of safety concerns in gene therapy experiments long ago. Lentiviruses can erroneously trigger cancer-causing mutations, a risk flagged by the Food and Drug Administration in the review of two Bluebird bio gene therapies and a reason they’re mostly involved in tightly controlled ex vivo processes. 

What advantages does in vivo cell therapy have over existing treatments? 

CAR-T therapies take weeks to produce. While patients wait, their disease can worsen or they might become too weak to receive treatment. They also require a “conditioning” chemotherapy regimen to prepare them for treatment, and monitoring for weeks afterwards to guard against potentially severe side effects. 

These hurdles have made CAR-T an expensive treatment primarily available at specialized centers and less accessible to people who live in rural areas or poorer nations. They’ve also weighed on the commercial outlook of other “ex vivo” gene-based treatments for inherited diseases like sickle cell and beta thalassemia, which are made with similarly complex manufacturing processes. 

An “in vivo” solution delivered through an infusion could be quicker and less costly to manufacture. Inside-the-body techniques could also provide an alternative to the “off-the-shelf” therapies involving donor cells, which have safety concerns and efficacy questions of their own. They might eliminate the need for chemotherapy conditioning regimens.

Some companies working on inside-the-body approaches aim to overcome the limitations of gene therapies that rely on adeno-associated viruses, or AAVs, to deliver their genetic cargo. While AAVs are widely used, the effects of the treatments they deliver may wane in cells that frequently divide. They can only carry a small amount of genetic material, too, and are sometimes targeted by the body’s defenses. 

What companies are working on in vivo cell therapy?

At least five startup companies have emerged since 2021 with technologies they claim are capable of producing in vivo cell therapies. 

Umoja was seeded by MPM Capital and DCVC Bio and formed by scientific researchers at Seattle Children’s Research Institute and Purdue University. It has since raised more than $260 million and brought its first drug candidate into clinical testing in May 2022. 

Ensoma officially launched in February 2021 alongside a wide-ranging partnership with Takeda that covers up to five experimental programs. It’s run by Emile Nuwaysir, the former CEO of Bluerock Therapeutics, a cell therapy startup Bayer bought in 2019.  

Interius BioTherapeutics followed in May 2021 with $76 million from Cormorant Asset Management and others including Bain Capital and Pfizer’s venture arm. The company is based on research by UPenn physician-scientist Saar Gill and is led by Phil Johnson, who was once chief scientific officer at The Children’s Hospital of Philadelphia. 

Vector BioPharma launched in August with $30 million from Versant Ventures and technology spun out of protein engineering expert Andreas Pluckthun’s lab at the University of Zurich. The month after, Capstan, co-founded by June, fellow CAR-T innovator Bruce Levine and mRNA pioneers Drew Weissman and Hamideh Parhiz, came out of stealth with the backing of five pharma companies. 

Publicly traded biotech Sana Biotechnology is also working on in vivo cell therapy. Novartis, meanwhile, is developing a CAR-T manufacturing process that minimizes the amount of work done outside the body, allowing modified cells to expand inside patients rather than in a lab.  

What is the status of their research? 

Most in vivo cell therapy work is still in early stages, though some developers have revealed details about their plans. 

Sana has more than half a dozen experimental treatments in preclinical testing for blood cancers and rare inherited diseases. It expects to ask the FDA in late 2022 to begin Phase 1 testing of one candidate being developed for two types of leukemia and non-Hodgkin lymphoma. 

Umoja’s first program, for a type of bone cancer tumors, is a typical ex vivo CAR-T treatment with a separately administered drug that “tags” tumor cells for destruction. The company could ask regulators as soon as in 2023 to begin human testing of two in vivo programs for solid tumors and blood cancers, according to its website.  

Vector expects to have “technical proof-of-concept” data in 2022 and animal data for its lead programs in 2023, it said in a statement. 

Capstan is starting with in vivo CAR-T therapies for diseases with no effective treatments, but plans to develop drugs for certain genetic blood disorders too. It hasn’t disclosed timelines. Neither have Ensoma or Interius, the latter of which is also looking at cancer immunotherapy.