Safe CAR-T: shedding light on CAR-related T-cell malignancies

As of September 30, 2023, the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database has received 12 reports of secondary T-cell malignancies since the first of the BCMA-/CD19-targeted autologous CAR-T therapies was approved in 2017 (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). Consequently, FDA has released a statement on November 28, 2023, announcing their ongoing investigation into the identified risk of T-cell malignancy, which has been associated with severe outcomes such as hospitalization and death. On April 18, 2024, the FDA mandated the inclusion of a boxed warning for T-cell malignancies following treatment with BCMA-/CD19-directed autologous CAR-T cell immunotherapies. In this commentary, we have thoroughly elucidated the possible mechanisms underlying theoretical tumorigenesis induced by current viral vectors. Furthermore, we have primarily proposed safer genetic engineering strategies for CAR-T cells, and underscored the necessity of introducing more sensitive and reliable safety evaluation indicators, such as T cell receptor (TCR) diversity and integration site analysis.