Does the evidence support safety concerns following CAR-T cell therapies?

Pharma News: The U.S. Food and Drug Administration (FDA) has launched an investigation into a concerning risk associated with CAR-T therapies, revealing a potential link between these highly effective oncology treatments and the development of secondary cancers in patients. The Therapeutic Goods Administration (TGA) is closely monitoring this situation.

The FDA disclosed that it is probing reports indicating the emergence of T-cell malignancies, including CAR-positive lymphoma, in patients who underwent BCMA- or CD19-directed CAR-T cell immunotherapies. Some individuals have either required hospitalisation or tragically died, the regulator confirmed. These cases have been identified both during clinical trials and post marketing surveillance of adverse events.

The implications extend to four CAR-T cell therapies approved for use in Australia. These include Janssen’s Carvykti (ciltacabtagene autoleucel) for relapsed or refractory multiple myeloma, Novartis’ Kymriah (tisagenlecleucel) for acute lymphoblastic leukemia (ALL) and relapsed or refractory diffuse large B cell lymphoma (DLBCL), as well as Gilead Sciences’ Tecartus (brexucabtagene autoleucel) for relapsed or refractory mantle cell lymphoma (MCL) and B-cell acute lymphoblastic leukemia (B-ALL), and Yescarta (axicabtagene ciloleucel) for relapsed or refractory large B-cell lymphoma.

Despite existing class warnings on the labels of CAR-T therapies regarding the potential risk of developing secondary cancers, the FDA’s investigation underscores the gravity of the situation. The agency clarified that the observed T-cell malignancies have manifested in patients who received various CAR-T products, necessitating an evaluation of potential regulatory actions.

“Patients and clinical trial participants receiving treatment with these products should be monitored lifelong for new malignancies,” emphasised the FDA in an official statement.

The suspected cancer risk is believed to emanate from the viral vectors used to administer cell and gene therapies. CAR-T therapies involve modifying a patient’s own T cells to target cancer cells via specific biomarkers like CD19 and BCMA. However, the viral vectors utilised in this process to deliver genetic modifications may inadvertently trigger cancer by inserting genetic material into the patient’s genome, particularly near cancer-related DNA sequences or suppressors.

A recent review of data from follow-up studies of CAR-T cell therapies demonstrated an incidence of secondary malignancies ranging from 4% to 16%.

“These incidences are not higher than expected given that all patients had a history of substantial chemotherapy exposure, which itself increases the risk of secondary malignancies,” said the authors of the review.

“These are not confirmed safety issues at this time and the TGA is closely monitoring evidence in this space,” stated the TGA. “This includes reviewing adverse event reports and medical literature, and liaison with international regulators for the four CAR-T immunotherapies that are registered on the Australian Register of Therapeutic Goods. If a safety issue is confirmed, then the TGA will take prompt regulatory action as appropriate.”

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