T-Cell Lymphomas in Recipients of CAR-T Cells: Assessing Risks and Causalities

The United States Food and Drug Administration (FDA) announcement in November 2023 regarding reports of the occurrence of secondary T-cell lymphomas in patients receiving chimeric antigen receptor T-cells (CAR-T) for B-cell malignancies resulted in widespread concern among patients, clinicians and scientists. Little information relevant to assessing causality, most importantly whether CAR retroviral or lentiviral vector genomic insertions contribute to oncogenesis, was initially available. However, since that time several publications have provided clinical and molecular details on three cases showing clonal CAR vector insertions in tumor cells but without firm evidence these insertions played any role in oncogenic transformation. In addition, several other cases have been reported without vector detected in tumor cells. In addition, epidemiologic analyses as well as institutional long-term CAR-T recipient cohort studies provide important additional information suggesting the risk of T-cell lymphomas following CAR-T therapies is extremely low. This review will provide a summary of information available to date, as well as review relevant prior research suggesting a low susceptibility of mature T-cells to insertional oncogenesis and documenting the almost complete lack of T-cell transformation following natural HIV infection. Alternative factors that may predispose patients treated with CAR-T cells to secondary hematologic malignancies, including immune dysfunction and clonal hematopoiesis, are discussed and likely play a greater role than insertional mutagenesis in secondary malignancies post-CAR therapies.