Black box warnings are to be added to CAR T therapies currently approved by the FDA because of the risk of secondary T-cell malignancies in patients. The FDA began investigating CAR Ts and T-cell malignancies in November 2023. In Europe, the EMA is also conducting its own investigation.
In letters sent to the affected manufacturers in January 2024, the FDA says, “We consider the serious risk of T cell malignancy to be applicable to all BCMA- and CD19-directed genetically modified autologous T cell immunotherapies.” The wording suggests a class-wide warning that could affect future therapies as they come to market.
For now, the therapies affected are Abecma (Celgene; BMS), Breyanzi (Juno; BMS), Carvykti (Janssen), Kymriah (Novartis), Tecartus (Kite), and Yescarta (Kite).
Writing in The New England Journal of Medicine, Nicole Verdun and Peter Marks from the FDA said, “As of December 31, 2023, the FDA had become aware of 22 cases of T-cell cancers that occurred after treatment with CAR-T products.”
Cases have been identified in association with five out of the six currently approved CAR T products, with the cancers generally manifesting within two years after CAR T administration. Verdun and Marks wrote, “In three cases for which genetic sequencing has been performed to date, the CAR transgene has been detected in the malignant clone, which indicates that the CAR-T product was most likely involved in the development of the T-cell cancer.”
The CAR T that does not yet seem to be associated with reported cases is Gilead’s Tecartus. A few days after the FDA posted its letters mandating a black box warning, it issued an amended letter for Tecartus. The warning acknowledges that T cell malignancies have occurred with CAR T products but removed the mention of Tecartus specifically. However, Tecartus must still include a labeling change with a black box warning that the product can increase the risk of other cancers.
The agency continues to investigate but says that it won’t be possible to determine whether the CAR construct triggered the cancer for every single case. Verdun and Marks also emphasized that the risk remains low: “With more than 27,000 doses of the six approved products having been administered in the United States, the overall rate of T-cell cancers among people receiving CAR T therapies appears to be quite low, even if all reported cases are assumed to be related to treatment.”
An article in Nature Medicine has also stressed that the risk is low “compared with other cancer treatments.”
Drug developers are already working on the next generation of CAR T products, with a focus on improving efficacy and safety. Verdun and Marks suggest that new “new strategies involving targeting insertion of the CAR construct to specific loci might help reduce the risk of cancers due to integration of the CAR construct at oncogenic loci within the genome.” In addition, tumor-testing could also provide new insight.
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