The European Medicines Agency EMA announces the launch of a review into the safety of anti-cancer CAR-Ts, personalized immunotherapies based on the patient’s T lymphocytes which are taken, reprogrammed to attack the tumor and then reinfused. The EMA’s PRAC Pharmacovigilance Committee, meeting from 8 to 11 January, decided to review the 6 Car-T products approved in the European Union, for the risk of “secondary malignancies related to T cells, including lymphoma and T-cell leukemia”.
The PRAC, informs the EMA, is examining “all available evidence, including information on 23 cases of various types of T-cell lymphoma or leukemia reported on EudraVigilance, the EU database of adverse drug effects”. Based on the results of the analysis, the panel will “decide on the need for any regulatory action.”
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6 Car-T-cells authorized in the European Union
The 6 Car-T-cells authorized in the European Union are Abecma*, Breyanzi*, Carvykti*, Kymriah*, Tecartus* and Yescarta*, lists the EMA. These medicines – recalls the EU regulatory body – are used to treat blood cancers such as leukemia and B-cell lymphoma, follicular lymphoma, multiple myeloma and mantle cell lymphoma, in patients whose cancer has come back or has stopped respond to previous therapy.
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A secondary neoplasm – specifies the EMA – is one that occurs when a patient who has a current or previous cancer develops a second tumor different from the first. For all 6 Car-T products mentioned above “secondary tumors were considered an important potential risk” already “at the time of their authorization” and for this reason they were “included in the risk management plans (RMP)”, points out the ‘agency. Therefore, “careful monitoring is already underway – assures the EMA – and the holders of the marketing authorization for approved medicines are required to regularly submit the provisional results of the long-term safety and efficacy studies imposed and as part of periodic safety update reports (Psur)”.
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“A normal practice that should not generate alarms”
“From the beginning, CAR-T therapies have been subjected to a very careful active surveillance process, but it is obvious that only widespread use by thousands of people can give us a real estimate of the risks – he tells Health Alessandro Rambaldi, Professor of Hematology at the University of Milan, Director of the Bone Marrow Transplant Program and of the Department of Oncology and Hematology of the Bergamo Hospital, among the leading Italian CAR-T experts – The appeal to the scientific community is therefore right, which also came from the FDA last December, to promptly report every case of secondary cancer and make every effort to rigorously ascertain any causal link with CAR-T therapy. At the same time, however, we must be very careful not to over-emphasize what is normal practice, and not to create alarmism about therapies that are saving many lives. In fact, it should be remembered that there have been very few cases of secondary tumors compared to thousands of patients treated. Patients who had no other treatment options.”
What does the potential risk depend on?
The concern, explains the expert, is linked to the process itself that leads to genetically modifying the T cells taken from the patient: “To prepare the CAR-T cells we use a viral vector that transports a gene inside the T cell. virus integrates into DNA in an only partially controlled way, and there is therefore a potential risk that it could damage genes crucial for cell proliferation and differentiation. These genes, when altered, can generate the development of tumors. This potential risk – known as insertional mutagenesis – is therefore linked to the very fact of genetically modifying a cell, and has already been observed in other gene therapies, for example in the treatment of immunodeficiencies. In that case – concludes Rambaldi – the target cells are hematopoietic stem cells, while in CAR-T cells the target of therapy is mature T lymphocytes, which greatly limits the risk of secondary events”.