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FDA investigating cancer risk linked to CAR-T cell therapy

The Food and Drug Adminsitration is investigating whether CAR-T cell therapies like Novartis’ Kymriah or Gilead’s Yescarta are linked to the risk of new blood cancers after receiving reports of so-called T cell malignancies in people who have received the treatments.

In a statement Tuesday, the agency said it’s weighing “the need for regulatory action” in response to the reports, which came from both clinical testing and safety monitoring tied to commercial use. The identified risk is applicable to all approved CAR-T therapies, although the agency noted that “the overall benefits of these products continue to outweigh their potential risks for their approved uses.”

The FDA approved the first CAR-T therapy, Kymriah, in 2017. Since then it has cleared five more from Gilead, Bristol Myers Squibb and Johnson & Johnson to treat people with advanced cases of leukemia, lymphoma or multiple myeloma. They’ve filled a void in treatment after standard drugs fail, but drugmakers have tested, and in some cases proved, their benefit earlier, when patients are less sick.

The therapies are built from a patient’s own T cells, which are collected and then genetically engineered with a “chimeric antigen receptor,” or CAR, that’s aimed at certain protein flags found on malignant cells. Once reinfused, the cells home in and destroy cancers that express that flag. (Currently approved therapies target flags known as CD19 and BCMA.)

Testing has shown they can generate deep and durable responses, sometimes lasting many years. They do come with side effects, most notably an immune-related condition called cytokine release syndrome that doctors can manage through careful monitoring in hospital.

Both drugmakers and the FDA have recognized that “secondary” malignancies are a risk for all CAR-T therapies, and the agency recommends treated patients should be monitored for life. Other cancer-fighting drugs like chemotherapy can also cause secondary malignancies.

The alert issued Tuesday stemmed from an unspecified number of reports received by the FDA, including of patients treated with CAR-T therapy who later developed “chimeric antigen receptor CAR-positive lymphoma.”

In a statement, Novartis said Kymriah has been used in more than 10,000 patients and “there is no evidence to date that would change our confidence in Kymriah’s benefit/risk profile.”

“As part of our continuous safety monitoring, Novartis has not identified a causal relationship between Kymriah and secondary malignancies. We are fully committed to patient safety and will continue to work with the U.S. Food and Drug Administration,” the statement read.

A Bristol Myers spokesperson stated its two drugs, Abecma and Breyanzi, have been used in 4,700 patients and the company “has not observed any CAR-positive T-cell malignancy cases.”

Stephan Grupp, head of the cellular therapy and transplant section at the Children’s Hospital of Pennsylvania, said that, among the 500 patients treated to date with CAR-T at CHOP or the University of Pennsylvania, none had developed the kind of T cell malignancy described by the FDA.

“We know for sure we’re not missing anything and we would certainly report any event like this, but we’d like to know what the broader world is seeing,” Grupp said in an email. “I think the real effect the FDA advisory will have is to increase the likelihood that voluntary reporting of these events happens.”

Grupp added that multiple lines of previous treatment with chemotherapy could in theory be tied to later T cell malignancies.

Dane Leone, an analyst at Raymond James who covers Bristol Myers Squibb, wrote in a note to clients how the FDA’s reference to chimeric antigen receptor CAR-positive lymphoma could indicate “the drug product itself is transforming into T cell lymphoma.”

“If this is true, we are surprised that the U.S. FDA has not issued any clinical holds for the currently approved [autologous] CAR-T therapies listed within the press release,” he wrote.


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