CBER Leaders Address Secondary Cancers After CAR T-Cell Therapy in NEJM Editorial

Leaders from the Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER) published an editorial in the New England Journal of Medicine last week describing the agency’s thinking on recent cases of T-cell malignancy occurring after treatment with chimeric antigen receptor (CAR) T-cell products.

In the editorial, Peter Marks, MD, PhD, CBER director; and Nicole Verdun, MD, director of CBER’s Office of Therapeutic Products, noted that while the current generation of approved CAR T-cell products show efficacy, they are also associated with well-described safety concerns. Accordingly, FDA issued a draft guidance (made final on Jan. 29) recommending that people who receive CAR T cells engineered with integrating vectors be monitored for extended periods for adverse events.

As of December 2023, FDA is aware of 22 cases of T-cell cancer occurring after treatment with CAR T-cell products, with evidence from genetic sequencing suggesting CAR-T presence in some cases. Marks and Verdun emphasized, however, that 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 appears low, even if all reported cases are assumed to be related to treatment.

Furthermore, while FDA is attempting to gather as much information as possible on the reported cases, Marks and Verdun noted that determining whether the T-cell cancer is associated with the CAR construct “most likely won’t be possible for every case reported to date.”

Marks and Verdun advised clinicians to report new cancers in patients receiving CAR T-cell therapy and to monitor patients for life due to uncertainty about the duration of risk. If a new cancer occurs after treatment with one of these products, clinicians should contact the manufacturer to report the event and obtain instructions to collect patient samples to test for the presence of the CAR transgene.

Marks and Verdun concluded that for now, secondary T-cell cancers occurring after treatment with CAR T-cell therapy appear to be relatively rare adverse events. Furthermore, they noted that appropriate product labeling will be a resource that helps clinicians manage conversations with patients about the benefits and risks associated with these treatment options.