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.

Carl June was desperate.

A first-of-its-kind cancer treatment June and his team at the University of Pennsylvania were developing had shown striking early results in three patients in a small clinical trial. But funding had dried up and June couldn’t afford to treat anyone else.

So June took a risk. He and his team wrote case reports on those first three patients, each of whom had received a cutting-edge treatment known as CAR-T cell therapy. They were sick with a form of leukemia that had evaded prior treatments, but all three went into remission after treatment — results so notable they were published in August 2011 in two major medical journals.

“It worked better than we ever thought it would,” said June, in an interview with BioPharma Dive. “That completely changed everything.”

June and his colleagues received thousands of requests from leukemia patients and even owners of sick pets to receive the treatment next. Offers from pharmaceutical companies and venture capitalists followed as the initial results were seen as a milestone in long-running efforts to make cell therapies for cancer. June’s program was licensed to Novartis and became the drug now sold as Kymriah.

Other therapies developed in the biotechnology startups Kite Pharma and Juno Therapeutics also reached market, stamping CAR-T as a powerful and potentially curative treatment.

Since then, funding hasn’t been a problem for June, whose next act has been to found biotech startups. One, Tmunity Therapeutics, has raised at least $175 million since 2015. Another that debuted in September, Capstan Therapeutics, has already secured $165 million. Both are part of a wave of companies trying to prove cell therapy can work in solid tumors and in autoimmune diseases.

“There’s an emerging cell therapy industry,” June said. “It’s a very exciting time.”

Challenges remain. The Food and Drug Administration in 2021 halted trials of Tmunity’s lead program for prostate cancer after two trial participants died. Capstan’s goal — to have the body make its own CAR-T cells with the help of messenger RNA — has never been attempted in humans. Other types of cell therapies based on different cell types or using alternate production techniques have shown limitations, too.

BioPharma Dive spoke with June about his experience founding startups and the future of the field. The following conversation has been lightly edited and condensed for clarity.

BIOPHARMA DIVE: Why did you license the treatment that became Kymriah to Novartis, rather than start a biotech around it?

CARL JUNE: That was a really big issue. We had offers from three large pharmas to in-license it to them, and then many offers to start a venture capital-based company. It was an ethical decision. Speed to market was important, because it was not a question of whether it would work, which it often is. By going to a pharma, there was no delay in building bricks and mortar and hiring people. They had a salesforce in place. We just had to teach their people to manufacture a cell therapy.

What did that experience teach you about working with a large organization?

JUNE: We had a mom-and-pop organization, and they had this army of people at Novartis. We had to learn how to interact. We were much more nimble in making decisions, and that's a real strength of biotech that I’ve now since realized.

The drawback of working with Big Pharma is large committees have to make decisions, rather than one person, like it used to be for us.

How did that impact your research?

JUNE: The license came in 2012, and then it became a high priority of ours to get this FDA approved in pediatric leukemia. And yet Kite [Pharma] — which was about two years behind us and had to put up the bricks and mortar and all that — caught up and was only [four] months behind us getting FDA approval. They played catch-up and really out-executed, as far as speed, what Novartis was able to do.

Did that influence your decisions since then to form biotech companies?

JUNE: Definitely. If you have a company that's singularly focused, it can be more nimble, and that's what I learned from the Kite versus Novartis experiments. Novartis has this huge portfolio and decision makers in Switzerland and Massachusetts. It just can't keep up with a highly focused team. That’s why I’ve gone now with Tmunity and Capstan. [Tmunity] has four [investigational new drug applications] that we’re filing this year. With Novartis, we couldn’t do that.

There have been setbacks as well for Tmunity. A clinical hold over safety. The company’s CEO left. Where do things stand?

JUNE: When you do Phase 1 trials, that's when you really learn what the toxicities are. Then you have to either kill the program, figure out how to manage the toxicities, or go back and engineer a new kind of T cell.

That’s what Tmunity has done. Tmunity has opened their trial [back] up with a modified CAR design now … Our trials [at UPenn] opened up at a lower dose. We're having efficacy, and manageable toxicity now. We'll see. In 2023 hopefully enough data will be made to get dosing set for a registration trial. I think prostate cancer might be the first solid cancer where CAR-T cells get FDA approval.

How did Capstan come together?

JUNE: Sometime in 2018, John Epstein, a cardiologist and developmental biologist, told me about finding that in injured hearts, these activated fibroblasts appeared that had fibroblast activation proteins. We had been building CARs against [those proteins], but for cancer. We started asking, ‘Can we target heart failure in mouse models?’ It was amazingly effective and published in Nature.

Then with Drew Weissman we started adapting [the process] to inject nanoparticles that can insert RNA into T cells in vivo and make CAR cells that can cause cardiac repair. That led to a paper in Science showing the feasibility of treating an animal model with in vivo CAR delivery.

Why form a new company around it?

JUNE: It’s a radically different manufacturing approach. What I have learned from Tmunity is, no biotech can really handle more than three or more projects at one time. Tmunity has four trials that are, or soon will be, open. There’s no way they could handle what we’re doing with Capstan. So that was an easy decision. It had to be a separate spin-out.

What makes in vivo CAR-T, particularly using mRNA, a challenge?

JUNE: Our immune system is primed to attack anything that’s delivering RNA. So the main challenge is, how do you make it stealth and get it into cells without causing a lot of immune activation? In the Science paper, we got 20% of the T cells in a mouse to express that CAR with a single injection. Will the profile be the same in humans as it is in mice, where we got very high levels of efficacy with very little toxicity?

What is your view of cell therapy’s potential for autoimmune disease?

JUNE: There was a Nature Medicine paper a couple of weeks ago where young women with refractory lupus, all between 20 and 24, had a response to CAR T cells that were made almost identically to the way we made them to treat leukemia. We don't yet know how long this will last or whether the toxicity is the same in patients with autoimmunity as they will be with cancer patients. It's very early days, but it’s exciting for the field to see this possibility now. It could be a paradigm shift if cell therapies have a curative effect for any type of severe autoimmune disease.

What about allogeneic, or ‘off-the-shelf,’ cell therapy? It’s further along than autoimmune cell therapy, but there are questions about how effective it is.

JUNE: I actually think we’re going to have both. Autologous cells are more complex, but we know now that they persisted, in our initial patients, for 10 years, acting as a true living drug.

Allogeneic cells won't do that, I don’t think, but they're going to be much more readily available. They’ll be better able to be used in more rural areas.

Can allogeneic cells be made to persist longer and match the durability of CAR-T?

JUNE: If you made a cell so that you couldn’t reject it, which is what you would have to do to have an allogeneic cell persist like the autologous cells would, that's actually a liability.

There is a whole class of viruses that can infect T cells. If you got an infection in one of these allogeneic cells that have been engineered so you can’t reject it, you would end up getting lymphoma. You actually don't want them to last long term. You want them to last at most, a few weeks and then get rejected or just go away so that they're not a liability long term. If the cells do persist long term, it's just a matter of time until it will happen.

Are there similar problems with natural killer-based cell therapies?

JUNE: They have a great promise but they're not designed to last long. NK cells last about a month — which is good. That’s actually a safety feature. They don’t cause graft-versus-host disease. They have an effect and then go away.

But in general, to have an actual clinical effect, they need to be a bridging therapy to a bone marrow transplant, other types of biologics, or even autologous cell therapy — to give you the time to make a precise engineered cell therapy. Because right now there's been a lot of patients [for whom] that time just isn't there. I think they’re actually mutually beneficial approaches and we’re going to see combinations of T cells and NK cells.

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Innovative cell and gene therapies could hold the keys to treating and potentially curing a wide range of genetic and acquired diseases. Among the arsenal of tools available to researchers and biopharmaceutical experts, lentiviral vectors have long been recognized as a versatile platform for delivering genetic material into target cells. However, as the field progresses and therapies move closer to clinical applications, addressing and overcoming common pitfalls associated with lentiviral cell and gene therapies becomes crucial.

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The precise determination of infectious viral titer is a critical factor in lentiviral cell and gene therapies, directly influencing treatment outcomes and patient safety. Inaccurate viral titer determination can lead to detrimental effects, including under-dosing or over-dosing of patients, potentially compromising the efficacy of treatments or causing adverse reactions.

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In addition to viral titer, cell and gene therapy developers need to know how efficiently their lentiviral vector integrates the gene of interest into the target cells. Failed transgene integration can offer no therapeutic effect, while vector copy numbers that are too high can result in overly potent and potentially dangerous products. In 2020, NIH researchers demonstrated the utility of ddPCR assays for assessing the average number of lentiviral vectors integrated into multiple types of engineered T cell therapies. In 2022, another group of researchers enabled greater industry standardization by developing lentiviral standards for determining vector copy number assay sensitivity, subsequently using these standards “to show the superior precision of Droplet Digital PCR over quantitative PCR for vector copy number determination.”

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The cancer cell therapy Carvykti dramatically outperformed standard drugs in a late-stage clinical trial testing its use in earlier treatment of the blood cancer multiple myeloma, according to data from a study abstract that was briefly posted online April 18.

The abstract showed Carvykti, which is made by Johnson & Johnson and Legend Biotech, reduced the risk of disease progression or death by 74% compared to standard of care — a degree of benefit that analysts who viewed it described as “stellar” and “highly encouraging.” 

J&J and Legend had previously said in late January that the study met its main goal, but did not disclose any specific data at the time. The abstract, which is no longer available online, was for presentation at the European Hematology Association’s annual meeting in early June. 

In an email, a spokesperson for J&J said the company could not confirm the data due to the embargo rules of the medical meeting where they will be presented. Stat News first reported news of the leaked data. 

Carvykti is what’s known as a CAR-T therapy, made from each patient’s immune cells, which are extracted and genetically reengineered to target proteins found on the surface of cancers. It’s currently approved in the U.S. for use treating multiple myeloma patients who have received at least four prior drugs. J&J and Legend aim to expand its approval into earlier “lines” of treatment and the study that the abstract details tested it among patients who had one to three prior therapies. 

Called CARTITUDE-4, the trial enrolled just over 400 patients and randomized them to receive either Carvykti or one of two cocktails of standard multiple myeloma drugs. According to analysts, the abstract showed data through a cut-off of Nov. 1, 2022, or a median of 16 months of follow-up post treatment. Median progression free survival — the study’s main goal — was not yet reached among the group getting Carvykti, compared to 12 months for those on standard of care. 

The 74% risk reduction those results represent “solidify Carvykti as the best-in-class cell therapy option for multiple myeloma,” wrote Leonid Timashev, an analyst with RBC Capital Markets, in a client note. 

Yaron Werber, an analyst at TD Cowen, described the benefit as “game-changing efficacy” that is “highly encouraging for adoption” in the second-line treatment setting. 

In the U.S., Carvykti competes with another CAR-T therapy called Abecma, made by Bristol Myers Squibb. The therapy, which targets the same BCMA protein as Carvykti, reduced the risk of disease progression and death by 51% in a generally similar trial, results of which were published in early 2023. (The two studies have some differences in design that make an apples-to-apples comparison more difficult.)

Bristol Myers’ application to expand Abecma’s approval is currently under review by the Food and Drug Administration, with a decision expected by December 2023. 

Both Bristol Myers and J&J have run into difficulties manufacturing their respective therapies, which as personalized treatments are complex to make and require careful shipping. On April 18, J&J disclosed first quarter sales results that were higher than expected, showing Carvykti earned $72 million between January and March.

“The manufacturing is ramping up to supply markets,” said J&J CFO Joe Wolk on an earnings conference call. “We have really tremendous demand given some of the data that supports this Carvykti, the CAR-T for Johnson & Johnson. And we’re committed to doing everything we can to accelerate our manufacturing abilities to meet that demand.” 

A week earlier, J&J and Legend entered into a manufacturing agreement with Novartis, another CAR-T developer, to help produce Carvykti.

Shares in Legend rose by double digits in April 19 trading on the Nasdaq stock exchange, while J&J’s stock rose less than 1%. 

Sales of Carvykti, a cell therapy used to treat multiple myeloma, were flat between the third and fourth quarters, according to fresh earnings numbers reported by its developers, Johnson & Johnson and Legend Biotech.

In a regulatory filing, Legend said that, based on information provided by J&J’s Janssen subsidiary, Carvykti generated $55 million in net sales from October through December. The therapy brought in the same amount during the three month period between July and September.

A J&J spokesperson said in an email that Carvykti’s sales are “in line” with the company’s expectations, adding that it continues to expand the network of centers offering the therapy in a “targeted, phased approach.” 

Carvykti is one of a growing class of drugs known as CAR T-cell therapies, which clinical trials have shown to be powerful weapons against certain blood cancers. The study which led to Carvykti’s approval, for example, tested the therapy in nearly 100 patients with multiple myeloma and found that after a median of about two years of treatment, 83% no longer had cancerous cells in their blood or bone marrow.

Despite being a valuable option for hard-to-treat cancers, CAR-T treatments have run into commercial obstacles.

One of the biggest has been producing enough of them to meet the demands of patients and physicians. Manufacturing CAR-T medicines is inherently difficult, requiring T cells to be collected from the patient, engineered to better fight cancer and then reinfused in a timely manner. But the process has become more challenging due to an industry-wide shortage of viral vectors, a key component for making CAR-T therapies.

On an earnings call this week, J&J CEO Joaquin Duato said demand for Carvykti has been “very strong,” and that the company is working to build up production capacity and expand its provider network.

In a Tuesday evening note to clients, Jefferies analyst Kelly Shi wrote that Carvykti’s sales trajectory is “largely in line” with her team’s expectations of conservative sales growth in the short term until the impact of that manufacturing expansion is realized later this year.

“As we scale our capabilities, we’re well positioned to ensure Carvykti is available to more patients who need it,” the company spokesperson said in response to a BioPharma Dive inquiry. 

In the near future, J&J and Legend hope to get Carvykti cleared for use in earlier lines of multiple myeloma treatment.

The medicine is currently approved for patients whose cancer progressed or came back after at least four other kinds of therapies. But a closely watched study named CARTITUDE-4 is pitting Carvykti against two other multiple myeloma treatment regimens, in patients who’ve previously received one to three drugs. Duato said that study will be “very important” for J&J to achieve its goals in multiple myeloma.

Initial data reported in January were positive, although the companies haven’t yet detailed the trial’s full results. 

The company already has three products for the cancer type — Carvykti, Darzalex and the recently approved Tecvayli — as well as an experimental medicine, talquetamab, that was submitted to the Food and Drug Administration for approval last month. This portfolio is “the most important growth driver for our pharmaceutical [division] moving forward,” Duato said.

“All in all, this portfolio enables us to do something very significant, which is changing the treatment paradigm,” he added.

Fellow CAR-T developers have seen sales grow after moving their therapies into earlier lines of treatment. Gilead, notably, reported in the third quarter that sales of its drug Yescarta had risen about 80% year over year, to $317 million, due in large part to an approval in the “second-line” setting for large B-cell lymphoma.

The Food and Drug Administration on June 23 approved a cancer cell therapy from Bristol Myers Squibb for earlier treatment of a common type of lymphoma, expanding the number of patients who could potentially receive the personalized drug.

The agency cleared Bristol Myers’ therapy, sold as Breyanzi, for patients whose large B-cell lymphoma is refractory to initial treatment or who relapse within a year, as well as those with relapsed or refractory disease who aren’t eligible for a stem cell transplant. 

The FDA's decision comes a little more than two months after the regulator granted a similar clearance to Gilead's competing cell therapy Yescarta.

Until this year, use of these cellular drugs, called CAR-T therapies, was limited to only after multiple other treatments failed to control patients' lymphoma. The approvals for Yescarta and Breyanzi make CAR-T available in the "second-line" setting, or following initial treatment.

Clinical testing showed both Yescarta and Breyanzi significantly outperformed chemotherapy and a stem cell transplant, considered standard of care for decades. In the trial run by Bristol Myers called Transform, Breyanzi reduced the risk of an "event" — cancer progression, subsequent treatment or death — by 65% versus chemo and transplantation. Breyanzi-treated patients went a median of 10 months without an event, compared to about two months for those in the control group, results showed.

The advancement of each therapy into earlier treatment lines, a larger market opportunity, could help change the narrative surrounding CAR-T treatments, sales of which have been slow to develop. Breyanzi has netted Bristol Myers $84 million since its launch in 2021 while sales of Yescarta, which was first approved in 2017, totaled $695 million in 2021.

Wall Street analysts have projected that second-line use in lymphoma could bring those numbers over $1 billion annually. Some 30% to 40% of patients relapse after initial treatment, and roughly half of them aren’t eligible for a stem cell transplant, said Nick Botwood, Bristol Myers’ head of U.S. medical affairs, in an interview.

“It’s a significant advancement over the standard of care,” Botwood added.

Yet, like Gilead, Bristol Myers will face challenges. While the combination of chemo and transplants often isn’t curative and causes several side effects, CAR-T treatments have toxicities as well — most notably, neurological and immune-related problems — and their administration is mostly limited to academic centers.

Broader use could renew debates about the price of the complex treatments, too. Breyanzi costs $410,000 and Yescarta $373,000, list prices that are meant to reflect their potentially long-lasting benefits. The treatments can also take weeks to manufacture, during which time patients may need another therapy or become too sick to receive CAR-T.

Bristol Myers, for instance, needs 24 to 33 days to make Breyanzi, according to Botwood. Gilead can produce Yescarta in less time, but still requires about two to three weeks. Each of them aim to do better, part of a broader effort to shorten CAR-T manufacturing times.

“Based on the progress we've been making to date, we’re confident our capacity will expand into the latter half of the year,” Botwood said. “We’re very much focused on continuous improvement.”

In the meantime, one factor in Bristol Myers’ favor is Breyanzi’s safety profile. Rates of a potentially deadly immune response associated with CAR-T therapy were lower than what’s been observed with other treatments, including Yescarta. And while its label requires patients to remain near treatment centers at least four weeks after an infusion, it also includes some leeway for outpatient use.

Bristol Myers obtained Breyanzi through its buyout of Celgene, which acquired the treatment’s original developer, Juno Therapeutics, in 2018. The company also sells a second cell therapy, a multiple myeloma treatment called Abecma, that was originally developed by Bluebird bio.

Bristol Myers Squibb is adding a viral vector production site in Libertyville, Illinois, to boost its manufacturing network for cancer cell therapies.

The New York-based drugmaker is taking over the facility and current plant employees from Novartis. A transition period will take place over the course of 2023, Bristol Myers said April 26.

In addition to an immediate increase in capacity for the drugmaker’s two existing CAR-T cell therapies, the company said the new manufacturing facility will help as it works to develop the next generation of treatments. “This development advances the company’s long-term ambitions in cell therapy,” Bristol Myers said.

Cell therapies are powerful weapons for treating some cancers, but the manufacturing required is complex and time-consuming. Bristol Myers has previously had difficulties producing enough of its two CAR-T cancer therapies to keep up with demand.

Bristol Myers won approval of both the lymphoma treatment Breyanzi and the multiple myeloma therapy Abecma in early 2021. They are personalized treatments that require a multi-week process during which a patient’s immune cells are extracted, shipped to a production site, genetically engineered to attack cancer and then reinfused into the patient.

Even as Bristol Myers has struggled with manufacturing, demand for the therapies has risen. Abecma sales jumped to $125 million in the fourth quarter of 2022, up from $69 million in the same period a year earlier. Breyanzi revenue climbed to $55 million from $40 million.

Executives say they are working to increase production capacity but are also highly mindful of maintaining quality in their processes. “These are complex drugs; they’re living products and you have to stay focused on your manufacturing success rate,” Christopher Boerner, executive vice president and chief commercialization officer, told investors on the company’s earnings call in February.

The facility in Libertyville specializes in viral vectors, benign viruses that are used to manipulate the immune cells into targeting cancer proteins. Novartis has used the Libertyville plant to produce its gene therapy Zolgensma in the past. However, in November 2022 the company said it would cease operations at the plant and lay off staff there.

Bristol Myers has cell therapy manufacturing facilities in Bothell, Washington; Warren, New Jersey; and Summit, New Jersey. It’s developing additional sites in Devens, Massachusetts, and Leiden, Netherlands.

A spokesperson for Bristol Myers confirmed in an email to BioPharma Dive that the company was leasing the facility from Novartis, and purchasing its assets. 

A biotechnology company looking to alleviate a problem in cell and gene therapy production emerged from “stealth” mode on April 11, unveiling itself alongside $64 million in funding.

Based in Philadelphia, VintaBio was founded by Junwei Sun and Shangzhen Zhou, two well-known researchers at the University of Pennsylvania. Both founders have been instrumental to the development of viral vectors — essential tools used to ship helpful genetic material into cells — that were part of cell and gene therapy treatments now on the market.

Sun and Zhou were on the team behind Luxturna, the first gene therapy approved by the Food and Drug Administration for an inherited disorder. Zhou was also involved with the development of Zolgensma, which treats the muscle-wasting disease spinal muscular atrophy, and the medicine that cured Emily Whitehead, who had acute lymphoblastic leukemia and was the first pediatric patient to receive what’s known as CAR-T cell therapy.

The medicine used to treat Whitehead would go on to be approved in 2017 under the brand name Kymriah.

As more companies entered the cell and gene therapy field, viral vector production became a bottleneck that has yet to be fixed. At VintaBio, the aim is to ease this bottleneck by manufacturing viral vectors. It’s an aim shared by other biotech startups, hospitals and large contract manufacturing organizations.

"I co-founded VintaBio to make sure viral vectors never prevent someone from receiving a life-changing treatment,” Zhou said in a statement, adding that the team at VintaBio wants to “provide the ability to scale cutting-edge therapies for thousands more in-need patients.”

VintaBio comes equipped with a 22,500-square-foot manufacturing facility in Philadelphia that’s now open and accepting orders from developers. The startup said construction of the facility was supported by the $64 million it raised — much of which came from Decheng Capital, an investment firm that focuses on early-stage life science companies.

VintaBio has also appointed David Radspinner as its CEO. Radspinner for years held leadership roles at Thermo Fisher Scientific and GE Healthcare, and, most recently, he served as president of biotherapeutics at the specialty manufacturing company ILC Dover.

A biotechnology startup has raised $200 million from a group of blue-chip investors to develop a new kind of cancer cell therapy for people with lymphoma whose cancer has relapsed or grown resistant to existing cellular treatments.

The cash influx will allow the startup, Cargo Therapeutics, to advance its therapy into a Phase 2 study later in 2023, as well as support the associated manufacturing work such a trial will require.

Cargo’s experimental treatment is a form of personalized cell therapy known as CAR-T. While several CAR-T therapies are approved in the U.S. to treat lymphoma, they all are aimed at a protein called CD19. Cargo’s therapy targets another protein called CD22 instead, which its backers see as a way around cancers that have returned or learned to evade CD19-directed treatment.

CAR-T therapy is now an important treatment option for several kinds of lymphoma, as well as certain leukemias and multiple myeloma. The treatments approved in the U.S. have mostly been reserved for use after multiple other drugs have failed to curb the cancer’s growth, although recent studies have proven CAR-T therapy’s benefit earlier and led to expanded clearances.

While some patients benefit greatly from CAR-T therapy, a good portion don’t, either never responding to treatment or having their cancer recede only to come back months later.

With lymphoma, for example, cancerous cells sometimes “escape,” losing the CD19 protein flag that CAR-T cells are trained to spot. When this happens, those cells can survive and grow without detection by the souped-up immune cell defenders.

Cargo is testing a different approach, focusing on the CD22 protein, or antigen, which is also expressed on cancerous B cells. “Targeting alternative antigens represents an important therapeutic strategy for patients who are [relapsed or refractory] to CAR19, including those with CD19 loss or downregulation,” wrote Gina Chapman, Cargo’s CEO, in an email.

In comparison to many new biotechs just starting out, Cargo has a leg up. Its treatment, dubbed CRG-022, has already been studied in a Phase 1 clinical trial and showed promise treating large B cell lymphoma that’s relapsed or resistant to CD19-directed CAR-T therapy.

Results from that trial were reported at a medical meeting in February and showed 68% of the 38 patients who were infused with Cargo’s therapy responded to treatment. Just over half went into remission, only one of whom has since relapsed.

Overall, patients lived a median of 22.5 months following treatment, according to an interim analysis of the data cited by Cargo.

The company is planning to advance its treatment into a larger study across multiple trial centers in 2023, which could potentially serve as the basis of an approval application should it succeed. “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,” said Reid Huber, a partner at Third Rock Ventures, which joined a dozen venture capital firms and other investors to fund the biotech.

Other groups are also trying to develop CD22-targeting CAR-T therapies. A federal database of clinical trials shows a number of studies ongoing testing various cellular treatments aimed at that protein, many by research hospitals in China. Four studies run by the National Cancer Institute in the U.S. are recruiting participants, while the British biotech Autolus lists a CAR-T therapy aimed at both CD19 and CD22 in early-stage development.

Cargo claims its treatment has a shot at being the best of its type, citing several design features that Chapman said could help improve T cell function, activation and persistence in the body.

While no CD22 CAR-T therapies are yet approved in the U.S., the Food and Drug Administration has cleared two drugs that target the protein: AstraZeneca’s Lumoxiti for a type of leukemia and Pfizer’s Besponsa for another type of the blood cancer. (AstraZeneca will soon withdraw Lumoxiti due to its low uptake.)

CAR-T therapies come with many side effects, some of which can be severe, and CRG-022 is likely to be no different. CD22 is also expressed on non-cancerous cells, so targeting the protein may result in what’s known as B cell aplasia, or extremely low B cell counts.

In addition to large B cell lymphoma, Cargo also plans to study CRG-022 in pediatric B-cell acute lymphoblastic leukemia.

Previously known as Syncopation Life Sciences, Cargo was launched in 2021. It was founded by Crystal Mackall, the founding director of the Stanford University Center for Cancer Cell Therapy; Robbie Majzner, an assistant professor of pediatrics there whose research has focused on CAR-T therapy; and Nancy Goodman, the CEO of Kids V Cancer, a pediatric cancer think tank.

The three collaborated with Samsara BioCapital to get Cargo off the ground. The most recent funding was led by Third Rock, RTW Investments and Perceptive Xontogeny Venture Fund, which were joined by seven new investors, Samsara, and the existing seed investors Red Tree Venture Capital and Emerson Collective.

Cancer cell therapy developer Adaptimmune Therapeutics is acquiring TCR2 Therapeutics in an all-stock deal, bringing together two struggling companies that have recently laid off staff. The combined company will have enough cash to fund operations until 2026.

Under the deal terms announced March 6, TCR2 shareholders will receive about 1.5 U.S.-listed Adaptimmune shares for each TCR2 share. After closing, Adaptimmune shareholders will own 75% of the combined company, which will continue to trade under the Adaptimmune ticker. TCR2 board members will have three seats on the nine-member board of directors.

Both companies are developing treatments that reengineer immune cells to fight cancer, attempting to build on the success of therapies like Novartis’ Kymriah and Gilead’s Yescarta. Adaptimmune aims to soon seek approval of its first product, a treatment for a rare type of soft tissue cancer, and expects to finish filing an application with the Food and Drug Administration in mid-2023.

The deal highlights the funding difficulties that development-stage biotechnology companies continue to face amid a sector-wide downturn that has weakened investor interest. This has led to a spate of layoffs and consolidation across the industry.

Before the companies’ respective layoffs — in November for Adaptimmune and in January for TCR2 — they both had expected to run out of money in 2024 without striking any licensing deals or stock sales.

If all goes to plan, by the end of 2024 the combined company should have an FDA decision in synovial sarcoma for the lead Adaptimmune product, called afami-cel, as well as late-stage data for a second product, called ADP-A2M4CD8. Mid-stage study data for a TCR2 product called gavo-cel could be available by the end of 2024 as well.

“The combination of our two companies not only sets the stage for near-term execution but also positions the new company for the longer-term,” TCR2 CEO Garry Menzel said in a statement.

Executives said the two companies have complementary technologies for turning T cells into potent cancer-fighting weapons, particularly for solid tumors that haven’t yet been addressed by cell therapies. Kymriah and therapies like it treat cancers of the blood and lymphatic system.

But, as with those therapies, the process for manufacturing Adaptimmune’s and TCR2’s products involves drawing blood from patients and isolating T cells to be engineered to kill tumor cells, and then re-infusing the cells back into patients. It’s a lengthy and costly process, but can deliver durable remissions when it works.

Other cell therapy companies have focused on “off-the-shelf” treatments that use donor cells, but progress in testing has been mixed. Meanwhile, another class of cancer drugs known as bispecific antibodies has advanced rapidly.

AstraZeneca on Nov. 29 agreed to buy privately held Neogene Therapeutics in a deal that represents the British drugmaker’s first significant acquisition in the field of cancer cell therapy.

Per deal terms, AstraZeneca will pay $200 million upfront for the startup, a developer of cell therapies for tough-to-reach solid tumors. AstraZeneca could add another $120 million in milestone payments if certain unspecified targets are met.

Formed in Amsterdam in 2018, Neogene is one of several companies to emerge in recent years with technology meant to improve on cell-based treatments. The biotech raised $110 million in venture financing in 2020 from a wide range of investors and, in May, was cleared by Dutch regulators to begin its first human trial.

Once a fringe area of cancer research, cell therapy has exploded over the last decade. Since 2017, several treatments have come to market for blood cancers like leukemia and multiple myeloma, establishing cell therapy as a new class of medicines.

Along the way, interest among large drugmakers has grown. Novartis and Gilead Sciences were some of the field’s earliest adopters, cutting deals that led to the first two CAR-T therapies to win approval, Kymriah and Yescarta. Bristol Myers Squibb and Johnson & Johnson followed with deals that have also produced marketed treatments.

And after a slow start, cell therapy sales are picking up, too, as studies prove the therapies’ benefit in earlier lines of treatment. Companies that weren’t previously involved, like Roche and AstraZeneca, are starting to enter the field as well.

As latecomers, AstraZeneca and Roche are focusing on newer approaches that attempt to overcome cell therapy’s limitations. Chief among these strategies are more convenient, “off-the-shelf” alternatives to personalized medicines like Kymriah, and expanding into solid tumors. Roche is working on off-the-shelf treatments with Poseida Therapeutics and Adaptimmune, and on solid tumor therapies with ArsenalBio, for example.

AstraZeneca has been pursuing similar ambitions more quietly. Fierce Biotech and Evaluate Vantage recently reported that the drugmaker has accelerated internal development and manufacturing efforts.

The Neogene deal puts a public stamp on its efforts, with Susan Galbraith, AstraZeneca’s head of oncology research, noting in a statement that the deal “complement[s] the cell therapy capability we have built over the last three years.”

Neogene was seeded by investors including Two River Ventures, a firm formed by cell therapy veteran and one-time Kite Pharma CEO Arie Belldegrun. The company is developing cell-based treatments designed to hunt for “neoantigens,” or unique protein flags that tumors acquire as they mutate. Neogene samples tumor cells, unearths targetable neoantigens, and then engineers cell therapies to simultaneously recognize several of them.

AstraZeneca believes the approach can unlock “targets previously inaccessible” to cell therapy, though that hasn’t been proven. Neogene’s most advanced program, known as NT-125, is expected to begin its first trial in 2023 in people with advanced solid tumors, according to results reported in November by one of its investors, Syncona.

The company’s research also includes early-stage work licensed from the National Cancer Institute and targeting mutations to the KRAS and TP53 genes, both well-known cancer targets.