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FDA launches wide probe into CAR-T therapy safety

The FDA has announced it will start an investigation into the safety of CAR-T therapies, after becoming concerned that they may be linked to the development of T-cell cancers.

The probe is directed at all CAR-Ts currently on the US market, including those that target CD19 as well as BCMA, which are used to treat a range of haematological malignancies including various forms of non-Hodgkin’s lymphoma, acute lymphoblastic leukaemia (ALL) and multiple myeloma.

In a statement, the FDA said it had received reports of T-cell malignancies – including chimeric antigen receptor (CAR) positive lymphoma – in patients who had received both types of CAR-T therapy.

The regulator highlighted the products by name, including Bristol-Myers Squib’s Abecma (idecabtagene vicleucel) and 2seventy bio-partnered Breyanzi (lisocabtagene maraleucel), Johnson & Johnson/Legen Biotech’s Carvykti (ciltacabtagene autoleucel), Novartis’ Kymriah (tisagenlecleucel) and Gilead/Kite’s Yescarta (axicabtagene ciloleucel) and Tecartus (brexucabtagene autoleucel).

“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 hospitalisation and death, and is evaluating the need for regulatory action,” said the regulator.

It points out that all autologous CAR-Ts, like other gene therapy products, use integrating vectors like lentiviral or retroviral vectors to modify cells in order to confer a therapeutic effect such as targeting specific cancer cells. That means there is a theoretical risk of off-target insertions which could introduce mutations that in turn could lead to cancer.

The investigation is notable in that all the approved CAR-Ts already include warnings of secondary malignancies on the labelling, and their approvals include a commitment to conduct 15-year long-term follow-up observational safety studies to assess their long-term safety and the risk they may cause cancer.

“Patients and clinical trial participants receiving treatment with these products should be monitored life-long for new malignancies,” said the FDA’s alert.

The announcement barely affected the share prices of the companies with CAR-Ts already on the market, but some others working on experimental CAR-Ts were hit, particularly those working on developing the technology for other non-cancer indications like autoimmune disease, where the risk-to-benefit threshold could be more difficult to meet.

Among these was Cabaletta Bio, working on a CAR-T therapy for lupus and other immunological disorders, whose shares lost around a third of their value following the announcement, while Gracell went down 17% and Cartesian Therapeutics fell 7%.

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