The underlying mechanism of chimeric antigen receptor (CAR)-T cell therapy triggering secondary T-cell cancers: Mystery of the Sphinx?

The U.S. Food and Drug Administration (FDA) has reported cases of T-cell malignancies, including CAR-positive lymphomas, in patients receiving B cell maturation antigen (BCMA)- or CD19-targeted autologous CAR-T cell immunotherapy. These reports were derived from clinical trials and/or post-marketing adverse event data. This finding has attracted widespread attention. Therefore, it is essential to explore the potential mechanisms by which chimeric antigen receptor (CAR)-T cell therapy triggers secondary T-cell cancers to further guarantee the safety of CAR-T cell therapy. •CAR-T cell therapy boosts the risk of causing a T-cell cancer when the retroviral or lentiviral vectors insertion sites are near DNA sequences associated with the cancer development.•The sustained T-cell activation signaling and inflammatory signaling environment in patients following CAR-T therapy may promote the growth of malignant clones.•Patients receiving CAR-T therapy are usually immunocompromised and potentially tumor-susceptible. The bridging therapy and lymphodepleting chemotherapy may lead to the development of treatment-related secondary cancers by causing DNA mutations.•Continually monitoring for potentially unknown serious side effects of CAR-T cells is certainly essential to take steps to avoid or mitigate off-target effects.