Related Articles
The US Food and Drug Administration says it is investigating cases in which some patients who received a type of cutting-edge cancer treatment later developed new cancers.
Known as CAR-T cell therapy, the treatment involves removing certain immune cells called T cells from patients and genetically modifying them to find and attack cancer. Since 2017, the FDA has approved six commercial CAR-T cell therapies, all for blood cancers such as leukemias and lymphomas. Researchers are also testing these promising therapies for a range of other cancers, as well as autoimmune diseases.
Now, the agency is probing reports of some patients’ T cells becoming cancerous after receiving these therapies. The FDA said in a notice on Tuesday that some patients have been hospitalized or have died following treatment, and the agency is evaluating the need for regulatory action.
These therapies are a last-line option when conventional treatments like chemotherapy and radiation don’t work. While they don’t always lead to a cure, CAR-T cell therapies have shown remarkable results against some of the most intractable cancers. Up to two-thirds or more of patients have gone into remission after getting CAR-T cell therapy, depending on the cancer type.
The first CAR-T cell therapy, Kymriah, was considered a breakthrough when it was approved six years ago. At the time, the FDA’s then commissioner, Scott Gottlieb, said: “We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer.” Kymriah debuted at an eye-popping price of $475,000, and more recently-approved CAR-T cell therapies are similarly priced.
The FDA announcement came as a surprise to David Porter, an oncologist and blood cancer expert at the University of Pennsylvania School of Medicine, where researchers pioneered CAR-T cell therapy. “We have not seen this at Penn,” he says, referring to cases of T cell cancers developing after treatment. The university has treated more than 800 patients with CAR-T cell therapies manufactured at Penn and hundreds more with commercially available treatments.
Most PopularGearThe Top New Features Coming to Apple’s iOS 18 and iPadOS 18By Julian ChokkattuCultureConfessions of a Hinge Power UserBy Jason ParhamGearHow Do You Solve a Problem Like Polestar?By Carlton ReidSecurityWhat You Need to Know About Grok AI and Your PrivacyBy Kate O'Flaherty
These therapies are made by adding genetic material to patients’ T cells in the lab, making them produce proteins on their surface called chimeric antigen receptors, or CARs. These CARS detect and bind to specific proteins on the surface of cancer cells, turning patients’ own cells into cancer assassins.
Scientists use harmless viruses to ferry and insert the new genetic material because of their natural ability to get inside cells. But the potential for these viruses to accidentally trigger another cancer has long been considered a theoretical risk. In its notice, the FDA said the use of these viruses may have played a role in patients developing secondary cancers.
The downside of using viruses is that they tend to drop off their genetic cargo at a random place in a person’s genome. Depending on where this new genetic material integrates, it could potentially activate a nearby cancer gene. “The concern would be that somehow the new genetic material that you put into patients’ T cells can induce cancer in that cell, perhaps by where it gets inserted in the DNA,” Porter says.
Because of this risk, the FDA currently requires that patients who receive CAR-T cell therapies be monitored for 15 years after treatment. In its notice on Tuesday, the agency suggested that “patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies.”
Maksim Mamonkin, an associate professor of pathology and immunology at Baylor College of Medicine who is involved in several clinical trials of CAR-T cell therapies, says he is not aware of cases in which engineered T cells became cancerous in the dozens of patients treated there. But he says no therapy is risk-free. “It doesn’t mean it isn’t possible,” he says. “It cannot be ruled out that, just by chance, the CAR gene ends up in the wrong location in the genome.”
Another explanation is that previous cancer treatments, including chemotherapy and radiation, played a role in the new T cell cancers patients developed. These treatments kill cancer cells, but they also damage DNA in healthy cells. In doing so, they can cause changes in cells that give rise to cancer later on.
“Very often, cancer is more than just one mutation, more than one insult,” Porter says. “So you may damage the DNA with prior chemotherapy or radiation, making that cell more prone. Should it have another event, then it’s well on the way already to becoming a cancer cell.”
A spokesperson for Novartis, which makes Kymriah, said that 10,000 patients have been treated with the therapy since its approval in 2017. The company has not seen any evidence to date that would change its confidence in the therapy’s risk-benefit profile. “As part of our continuous safety monitoring, Novartis has not identified a causal relationship between Kymriah and secondary malignancies,” a spokesperson told WIRED via email.
A representative for Bristol Myers Squibb, which manufactures two approved CAR-T cell therapies, Abecma and Breyanzi, wrote that the company is aware of the FDA’s investigation. More than 4,700 patients have received the therapies, either in research trials or as commercial products. “To date, BMS has not observed any CAR-positive T-cell malignancy cases and therefore, we have not found a causal relationship between our products and secondary malignancies,” the spokesperson told WIRED by email.
Most PopularGearThe Top New Features Coming to Apple’s iOS 18 and iPadOS 18By Julian ChokkattuCultureConfessions of a Hinge Power UserBy Jason ParhamGearHow Do You Solve a Problem Like Polestar?By Carlton ReidSecurityWhat You Need to Know About Grok AI and Your PrivacyBy Kate O'Flaherty
Johnson & Johnson, which makes another FDA-approved therapy, Carvykti, said through a spokesperson that the company is committed to the health and safety of patients. “We have shared our data with the FDA and are working with the agency as they assess this newly identified class-effect safety signal,” a spokesperson told WIRED in an email. More than 2,000 patients have been treated with Carvykti, they wrote.
Kite Pharma, a unit of Gilead, makes the two other commercial therapies, Tecartus and Yescarta. When reached via email, a Gilead representative said that the company is confident in the safety profile of its products, having treated 17,700 patients. “We are not aware of any evidence to date that treatment with Yescarta or Tecartus has a causal role in the development of these malignancies of T-cell origin,” the representative wrote. They added that the company has a rigorous process for safety monitoring and has fully cooperated with the FDA’s request for data on its products.
In yesterday’s statement, the FDA wrote that “the benefits of these products continue to outweigh their potential risks.”
Porter agrees. “Clearly, this is concerning and we need more information,” he says. “But it’s likely to be a rare phenomenon.”
Update 11-30-2023 12:53pm ET: This story was updated to add a comment from a Gilead representative.
