The effort to make a breakthrough cancer therapy cheaper

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CAR-T therapies, created by engineering a patient's own cells to fight cancer, are typically reserved for people who have exhausted other treatment options. But last week, the FDA approved Carvykti, a CAR-T product for multiple myeloma, as a second-line therapy. That means people are eligible to receive Carvykti after their first relapse.

While this means some multiple myeloma patients in the US will now get earlier access to CAR-T, the vast majority of patients around the globe still won't get CAR-T at all. These therapies are expensive-half a million dollars in some cases. But do they have to be?

Today, let's take a look at efforts to make CAR-T cheaper and more accessible.

It's not hard to see why CAR-T comes with a high price tag. Creating these therapies is a multistep process. First doctors harvest T cells from the patient. Those cells are then engineered outside the body using a viral vector, which inserts an artificial gene that codes for a chimeric antigen receptor, or CAR. That receptor enables the cells to identify cancer cells and flag them for destruction. The cells must then be grown in the lab until they number in the millions. Meanwhile, the patient has to undergo chemotherapy to destroy any remaining T cells and make space for the CAR-T cells. The engineered cells are then reintroduced into the patient's body, where they become living, cancer-fighting drugs. It's a high-tech and laborious process.

In the US, CAR-T brings in big money. The therapies are priced between $300,000 and $600,000, but some estimates put the true cost-covering hospital time, the care required to manage adverse reactions, and more-at more than a million dollars in some cases.

One way to cut costs is to produce the therapy in countries where drug development and manufacturing is significantly cheaper. In March, India approved its first homegrown CAR-T therapy, NexCAR19. It's produced by a small biotech called ImmunoACT, based in Mumbai. The Indian CAR-T therapy costs roughly a tenth of what US products sell for: between $30,000 and $50,000. It lights a little fire under all of us to look at the cost of making CAR-T cells, even in places like the United States," says Terry Fry, a pediatric hematologist at the University of Colorado Anschutz Medical Campus.

That lower cost is due to a variety of factors. Labor is cheaper in India, where the drug was developed and tested and is now manufactured. The company also saved money by manufacturing its own viral vectors, one of the most expensive line items in the manufacturing process.

Another way to curb costs is to produce the therapies in the medical centers where they're delivered. Although cancer centers are in charge of collecting T cells from their patients, they typically don't produce the CAR-T therapies themselves. Instead they ship the cells to pharma companies, which have specialized facilities for engineering and growing the cells. Then the company ships the therapy back. But producing these therapies in house-a model called point-of-care manufacturing-could save money and reduce wait times. One hospital in Barcelona made and tested its own CAR-T therapy and now provides it to patients for $97,000, a fraction of what the name-brand medicines cost.

In Brazil, the Oswaldo Cruz Foundation, a vaccine manufacturer and the largest biomedical research institute in Latin America, recently partnered with a US-based nonprofit called Caring Cross to help develop local CAR-T manufacturing capabilities. Caring Cross has developed a point-of-care manufacturing process able to generate CAR-T therapies for an even lower cost-roughly $20,000 in materials and $10,000 in labor and facilities.

It's an attractive model. Demand for CAR-T often outstrips supply, leading to long wait times. There is a growing tension around the limited access that we're seeing for cell and gene therapies coming out of biotech," Stanford pediatric oncologist Crystal Mackall told Stat. It's incredibly tempting to say, Well, why don't you just let me make it for my patients?'"

Even these treatments run in the tens of thousands of dollars, partly because approved CAR-T products are bespoke therapies, each one produced for a particular patient. But many companies are also working on off-the-shelf CAR-T therapies. In some cases, that means engineering T cells from healthy donors. Some of those therapies are already in clinical trials.

In other cases, companies are working to engineer cells inside the body. That process should make it much, much simpler and cheaper to deliver CAR-T. With conventional CAR-T therapies, patients have to undergo chemotherapy to destroy their existing T cells. But with in vivo CAR-T, this step isn't necessary. And because these therapies don't require any cell manipulation outside the patient's body, you could take it in an outpatient clinic," says Priya Karmali, chief technology officer at Capstan Therapeutics, which is developing in vivo CAR-T therapies. You wouldn't need specialized centers."

Some in vivo strategies, just like the ex vivo strategies, rely on viral vectors. Umoja Biopharma's platform uses a viral vector but also employs a second technology to prompt the engineered cells to survive and expand in the presence of the drug rapamycin. Last fall, the company reported that it had successfully generated in vivo CAR-T cells in nonhuman primates.

At Capstan Therapeutics, researchers are taking a different tack, using lipid nanoparticles to ferry mRNA into T cells. When a viral vector places the CAR gene into a cell's DNA, the change is permanent. But with mRNA, the CAR operates for only a limited time. Once the war is over, you don't want the soldiers lurking around forever," Karmali says.

And with CAR-T, there are plenty of potential battlefields to conquer. CAR-T therapies are already showing promise beyond blood cancers. Earlier this year, researchers reported stunning results in 15 patients with lupus and other autoimmune diseases. CAR-T is also being tested as a treatment for solid tumors, heart disease, aging, HIV infection, and more. As the number of people eligible for CAR-T therapies increases, so will the pressure to reduce the cost.

Now read the rest of The CheckupRead more from MIT Technology Review's archive

Scientists are finally making headway in moving CAR-T into solid tumors. Last fall I wrote about the barriers and the progress.

In the early days of CAR-T, Emily Mullin reported on patient deaths that called the safety of the treatment into question.

Travel back in time to relive the excitement over the approval of the first CAR-T therapy with this story by Emily Mullin.

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