Ignacio Melero
Professor of Immunology at the University of Navarra, CIMA researcher and co-director of the Department of Immunology and Immunotherapy at the Clínica Universidad de Navarra.
This is a retrospective study of patients treated with CAR-T cells (CAR19) for the treatment of lymphomas. In a series of more than 700 patients, only one secondary lymphoma was detected, but it is not formed by CAR-T cells and does not have insertional mutagenesis (by insertion of the CAR gene encoded by the corresponding lentiviral vector). The cause of the second lymphoma is related to the clonal haematopoiesis mutations that the patient had as a predisposing factor and very possibly to the Epstein Barr virus.
An important message is that the risk of malignant transformation of CAR-T cells is not zero, but probably very low. The risk-benefit balance is clearly very favourable if we are talking about treating leukaemias, lymphomas or myelomas, but could become questionable for the treatment of autoimmune diseases, especially in children, such as neonatal systemic lupus erythematosus. This work suggests that the risk of CAR-T cell-derived T-cell lymphomas should be very low and possibly tolerable in these indications for non-malignant diseases.
This paper argues in that direction and the authors do excellent molecular detective work to prove beyond doubt that the second lymphoma in one of the patients does not consist of transformed CAR-T cells.