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.

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. 

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Regulatory agencies worldwide, including the Food and Drug Administration (FDA), European Medicines Agency (EMA) and China’s National Medical Products Administration (NMPA), are facing a sharp increase in complex cell and gene therapy (CAGT) product applications. At the same time, clinical holds issued by the FDA have risen by 12.5% year-on-year, with the agency imposing 747 from January through mid-December of 2022.^[1] Agency officials said the uptick is likely driven by CAGTs, prompting a congressional inquiry.^[2] Since the FDA sits at the apex of the global CAGT regulatory framework, its clinical hold decisions typically cascade to other regions. 

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Precaution: Design a phase-appropriate CMC road map

Pitfall #2: Submitting an unwieldy IND application
Precaution: Develop a disciplined scientific and clinical rationale

Pitfall #3: Being ill-prepared for EMA meetings
Precaution: Know the guidelines

Pitfall #4: Unfamiliarity with China’s CAGT regulatory framework
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References

[1] Essley Whyte, L. (2023) “FDA Increasingly Halting Human Trials as Companies Pursue Risky, Cutting-Edge Drugs.” The Wall Street Journal, 10 January 2023.  Available at: https://www.wsj.com/articles/fda-increasingly-halting-human-trials-as-companies-pursue-risky-cutting-edge-drugs-11673322324. (Accessed April 19, 2023)

[2] Eshoo, A. and Guthrie, B. (2023) Letter to Peter Marks, M.D., Director, Center for Biologics Evaluation and Research. 26 March 2023. Available at: https://guthrie.house.gov/uploadedfiles/fda_cell_and_gene_therapy_cber_letter_3.26.23.pdf. (Accessed April 19, 2023)

Cellares, a biotechnology startup that bills itself as the first “integrated” development and manufacturing organization dedicated to cell therapy, raised $255 million in a Series C financing.

The pharmaceutical giant Bristol Myers Squibb joined other investors including Koch Disruptive Technologies, DFJ Growth and Willett Advisors to fund the latest round. Existing investors Eclipse, Decheng Capital and 8VC also participated, Cellares said in late August. 

David Mauney, managing director at Koch Disruptive Technologies, will join the board of directors at Cellares as part of the financing deal. He joins co-founders Fabian Gerlinghaus and Omar Kurdi and partners from Eclipse and Decheng on the board. The company’s advisory board includes cell therapy pioneer Carl June and Ezekiel Emanuel, a leading bioethicist who helped craft the Obamacare law.

The enthusiasm for a company dedicated to cell and gene therapy manufacturing stands out at a time when biotech startups are struggling to raise funding.

The field is booming, with more than 2,200 clinical trials underway, according to the Alliance for Regenerative Medicine. But manufacturing for cell and gene therapies is complex, expensive and time-consuming. Small startups usually don’t have the capacity to handle production on their own, and larger contract manufacturing groups haven’t been able to handle all the demand from industry.

Enter a large and lengthening list of startups, among them Cellares, Elevate Bio, Kincell Bio and VintaBio, touting different ways of solving the problem. Some are manufacturing the delivery tools often used in gene and cell therapy experiments, while others are offering broader services, such as consulting and development assistance.

Cellares touts its “smart factories” that take advantage of automated machinery to produce more batches of both “off-the-shelf” cell therapies and personalized treatments that are formulated from a patient’s own cells. It plans to cater to both clinical-stage companies and those who need industrial-scale manufacturing.

The first Cellares smart factory, in South San Francisco, should be ready for regulatory compliant manufacturing in the first half of next year, while another in Bridgewater, New Jersey, is set to debut in the second half of 2024. The Bridgewater plant will be able to produce as many as 40,000 batches of cell therapy a year, 10 times as much as a traditional CDMO, Cellares said.

Cellares also plans to break ground on a smart factory in Europe next year.

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.

AstraZeneca will work with biotechnology startup Quell Therapeutics to develop cell-based treatments for autoimmune diseases, the latest in a string of recent deals involving an emerging form of cell therapy.

Under terms of a deal announced June 9, AstraZeneca and Quell will co-develop regulatory T cell, or “Treg,” cell therapies for Type 1 diabetes and inflammatory bowel disease. AstraZeneca will pay Quell $85 million in cash and equity, and could add up to $2 billion in future payments if the programs hit certain milestones.

In return, AstraZeneca receives an option to further develop and commercialize any candidates that progress, though Quell can opt to split U.S. rights to the Type 1 diabetes program.

The deal is another signal of AstraZeneca’s interest in cell therapy. Though the British drugmaker has built a significant presence in oncology, it’s been a latecomer to cell therapy, a field of research that’s gained significant ground in recent years. Since 2017, several medicines have been approved for blood cancers like leukemia and multiple myeloma, and are now being studied and cleared for broader use.

AstraZeneca wasn’t part of that initial wave of research. But it has reportedly been quietly building internal development and manufacturing capabilities, and in 2022 signed its first significant deal, an alliance with Neogene Therapeutics. That alliance focused on cell therapy’s limited ability to reach into solid tumors.

AstraZeneca is building on those efforts by aligning with Quell. The startup is one of the most well-funded of a growing group of companies developing “Treg” cell therapies. These treatments harness Tregs, immune cells different from the ones used in cancer cell therapies. Tregs help protect the body against the wayward immune attacks that lead to inflammatory conditions.

Treg cell therapies are designed to try to rebalance the immune systems of patients with autoimmune conditions such as inflammatory bowel disease. The hope is they could produce long-lasting effects and avoid weakening peoples’ immune systems as many current autoimmune therapies do.

Though research remains early — one of the most advanced treatments, from Sangamo Therapeutics, is in a Phase 1 trial — the approach has intrigued some large drugmakers. Since 2020, Gilead, Bristol Myers Squibb and Regeneron Pharmaceuticals have either formed collaborations with or invested in Treg cell therapy startups. Like AstraZeneca, Bristol Myers and Regeneron signed those partnerships to develop treatments for inflammatory bowel disease.

The Quell deal “is aligned with our strategy to target underlying disease drivers to stop or slow disease progression and ultimately accelerate the delivery of transformative care to patients with chronic autoimmune conditions,” said Mene Pangalos, AstraZeneca’s head of biopharmaceuticals R&D, in a statement.

Johnson & Johnson expects its cancer cell therapy Carvykti to become a go-to option for treating multiple myeloma earlier, presenting in early June a fuller look at clinical trial results that show the therapy substantially outperformed the current standard.

In the trial, Carvykti reduced the risk of disease progression or death by 74% versus one of two commonly used drug combinations in patients for whom a mainstay medicine called Revlimid no longer works. According to J&J, it’s the largest relative risk reduction to be reported in a Phase 3 study of a treatment for the blood cancer.

Fragments of the data leaked in April, when an abstract of the study was inadvertently posted online. On June 5, researchers are presenting detailed findings at the American Society of Clinical Oncology’s annual meeting.

The data hold up to the closer inspection, affirming Carvykti’s potential to be used after Revlimid fails, rather than reserved for only after several treatments do. J&J intends to use the data to seek an expanded approval, which would substantially broaden the cellular drug’s market.

“[Carvytki] has not only shown that it delivers remarkably effective outcomes compared to patients’ current options, but also that it can be used safely earlier in the treatment phase,” said Oreofe Odejide, a medical oncologist at Dana-Farber Cancer Institute, in a statement provided by ASCO.

J&J’s study, called CARTITUDE-4, enrolled 419 people with multiple myeloma that no longer responded to Revlimid. Some had received one or two other treatments in addition to Revlimid, too. Once enrolled, half received Carvykti after interim, or “bridging,” treatment with a cocktail of multiple myeloma therapies, while the other half received one of two three-drug regimens.

Overall, 84% of the trial participants assigned to receive Carvykti responded, seeing their blood cancer counts recede, compared to 67% given standard treatment. However, 32 people were not able to receive J&J’s drug, due to their disease progression or death. Of the 176 who actually did get the treatment, 175 responded — a 99% response rate.

Nearly four times as many people on Carvykti as on standard drugs achieved a measure of cancer response known as “minimal residual disease negative,” indicating no cancer cells were found after treatment.

“I think the data speak for themselves,” said Mark Wildgust, head of global medical affairs in oncology for J&J’s Janssen unit. “A single infusion significantly prolongs progression-free survival, and does so versus a highly effective standard of care.”

Binod Dhakal, an associate professor at the Medical College of Wisconsin and the study’s lead investigator, described the data in an ASCO press conference as “setting a new efficacy bar” in relapsed, refractory multiple myeloma.

Still, Carvykti does come with considerable side effects, including infections, low blood cell counts, neurological toxicity and a potentially dangerous immune reaction known as cytokine release syndrome, or CRS. Approximately three-quarters of participants who received Carvykti developed CRS, although notably only two cases were rated as severe.

Carvykti is what’s known as a CAR-T therapy. Made from the immune cells of each patient, these personalized treatments are engineered to target telltale proteins on the surface of cancer cells. In Carvykti’s case, it’s a protein known as BCMA.

J&J, which co-developed Carvykti with a biotechnology company called Legend, won U.S. approval of the drug in February 2022 for multiple myeloma patients whose cancer had relapsed or become resistant to at least four prior drugs.

The ASCO data should support earlier use, potentially after only one relapse, according to Wildgust. “CARTITUDE-4 should support an approval application in patients who have had one to three prior lines of therapy and are [Revlimid] refractory,” he said. “That represents a large portion of patients.”

Yet hanging over J&J’s expansion plans are manufacturing challenges that have constrained Carvykti’s availability in the U.S. Due to their personalized nature, CART- therapies are hard to produce, requiring an exacting supply chain and intensive processing before being infused into patients. Some components used to make them have been difficult to obtain in large quantities.

Since launching Carvykti, J&J has had to take a phased approach, allocating supply to a limited, but growing, number of treatment centers.

Meredith Unger, head of marketing and operations for Janssen’s U.S. CAR-T business, said the company has increased its supply substantially since the end of last year, allowing it to raise the number of allotted treatment slots per center by 50%.

Additionally, the company has begun to make additional slots available to centers if they have patients who need treatment before their next allocation, Unger said.

“We are working as hard as we can to get capacity going to meet demand, not only for the indications we’re approved for today, but [also] the indications we anticipate coming,” Unger said.

Carvykti shares the market with another CAR-T therapy, developed by Bristol Myers Squibb and sold as Abecma. Manufacturing challenges have also hampered Bristol Myers’ ability to supply the drug, although sales have grown in recent quarters.

Approved for late-line use, Abecma is currently under Food and Drug Administration review for earlier treatment in multiple myeloma patients who have previously received three commonly used types of drugs. A decision is expected by mid-December.

Beyond CAR-T, the pipeline of experimental multiple myeloma drugs being developed is deep, and includes two dual-targeting antibodies from J&J. People with the blood cancer often cycle through different treatments, which typically work for a time but aren’t typically curative.

Cell therapies could offer the potential for longer-lasting remission. At ASCO, J&J and Legend are also presenting follow-up data from two earlier studies of Carvykti and a precursor version of Carvykti, given later after many treatments had failed. Participants in one of the trials, dubbed LEGEND-2, lived a median of 56 months after treatment, while follow-up data from the second, CARTITUDE-1, showed nearly half of patients had no disease progression after three years.

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.