What is CAR T-cell therapy?

In CAR T-cell therapy, a type of white blood cell called T cells are removed from a patient's blood before being genetically modified to make proteins called chimeric antigen receptors (CAR). These receptors allow T cells to target and destroy cancer cells. The genetically modified T cells are then infused back into a patient's blood.

So far, FDA has approved CAR T-cell therapies to treat several types of leukemia and lymphoma, as well as multiple myeloma, and clinical trials are ongoing for a range of other cancers. According to cancer specialists, these treatments have helped save the lives of thousands of blood cancer patients.

However, like other cancer treatments, including radiation and chemotherapy, CAR T-cell treatments also have a risk of secondary cancers. During the initial approval of CAR T-cell therapies in 2017, FDA included a warning on prescribing information and required drug manufacturers to conduct 15-year safety studies.

FDA investigates potential cancer risk from CAR T-cell therapy

On Tuesday, FDA announced that it was investigating whether CAR T-cell therapy could potentially cause lymphoma, a blood cancer. According to the agency, it has received 19 reports of CAR-associated T cell malignancies. Of these reports, five were from clinical trials, and 14 were from FDA's adverse event reporting system.

All six currently approved CAR T-cell therapies are included in the investigation:

• Bristol Myers Squibb's Abecma and Breyanzi
• Johnson & Johnson's Carvykti
• Novartis' Kymriah
• Gilead Sciences' Yescarta and Tecartus

"Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action," agency officials said.

In response to FDA's announcement, experts in CAR T-cell therapy said they were surprised by the investigation and had not previously seen data on the risk of secondary cancers.

"This is an early report of the first cases of autologous T cell transformation," said Carl June, a professor at the University of Pennsylvania who helped develop the CAR T-cell technology. "Scientifically, it will be important to learn if these cases had preexisting clonal hematopoiesis that may predispose to this adverse event. It is likely that previous treatment with cytotoxic chemotherapy may render patients more susceptible to this event."

For their part, drug manufacturers have said they have not observed the development of any secondary cancers in patients using their CAR T-cell products, but are committed to ensuring patient safety.

"Patient safety is a top priority for [Bristol Myers Squibb], and we remain confident in the safety profile and clinical value of our cell therapies," the company said. "We are collaborating with the FDA in its ongoing investigation and are responding to FDA's requests for information."

Although the risk of secondary cancers from CAR T-cell therapies is serious and warrants close investigation, Marcela Maus, a cell therapy researcher at Mass General Cancer Center, said she hoped FDA would not implement longer follow-up periods for CAR T-cell research.

"As an oncologist, we treat patients with things like chemotherapy and radiation which also have a risk of future malignancy, and it's not well defined," Maus said. "I would be very disappointed if this field was single bound as riskier than others if it has a very low frequency of events."

Overall, many health experts say the benefits of CAR T-cell therapies continue to outweigh their potential risks. "I firmly believe that these therapies offer tremendous value to patients, curing those without other viable treatment options and improving survival in the case of lymphoma," said Frederick Locke, a principal investigator of CAR T-cell therapies from the Moffit Cancer Center. (Chen et al., STAT+ [subscription required], Vinluan, MedCity News, 11/28; Bankhead, MedPage Today, 11/29; Kolata, New York Times, 11/28; Chen, STAT+ [subscription required], 11/29; Bettelheim, Axios, 11/29; Shoaib, Wall Street Journal, 11/28)

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