Dual targeting CAR-T cells for B-cell acute lymphoblastic leukaemia and B-cell non-Hodgkin lymphoma

Relapse after CD19-directed chimeric antigen receptor (CAR)-T cell therapy remains a major challenge in B-cell acute lymphoblastic leukaemia (ALL) and B-cell non-Hodgkin lymphoma (B-NHL). One of the main strategies to avoid CD19-negative relapse has been the development of dual CAR-T cells targeting CD19 and an additional target, such as CD22 or CD20. Different methods have been used to achieve this, including co-administration of two products targeting one single antigen, co-transduction of autologous T-cells, use of a bicistronic vector or the development of bivalent CARs. Phase 1 and 2 trials across all manufacturing strategies have shown this to be a safe approach with equivalent remission rates and initial product expansion. CAR-T cell persistence remains a significant issue, with a majority of antigen-positive relapses after CAR-T cell infusion. Further, despite adding a second antigen, antigen-negative relapses have not yet been eliminated. This review will summarise the state-of-the-art with dual targeting CAR-T cells for B-cell ALL and B-NHL, challenges encountered, and possible next steps to overcome them.