RESEARCHERS have developed a promising new CAR T cell platform, ALA-CART, which could significantly improve the treatment of relapsed and refractory leukaemia, particularly in cases where current therapies fail. Chimeric antigen receptor (CAR) T cells have shown success in treating leukaemia, but relapses often occur due to the inability of second-generation CAR T cells to effectively target antigen-low cells, a key issue in CD22BBz CAR T cell therapy.
In a recent study, scientists discovered that antigen-low stimulation led to inefficient phosphorylation of the linker for activation of T cells (LAT), which limited downstream signalling and weakened the CAR T cell response. To address this, the team developed the ALA-CART platform, which incorporates a LAT-activating CAR to restore LAT activity and enhance cell signalling.
The new platform demonstrated improved LAT phosphorylation, MAPK signalling, and AP-1 activity, which resulted in enhanced cytotoxicity, proliferation, and persistence of CAR T cells. Importantly, ALA-CART cells showed reduced differentiation during manufacturing and exhibited greater efficacy against antigen-low leukaemias that were previously refractory to traditional CD22BBz CAR T cells.
The ALA-CART platform represents a significant advancement in CAR T cell therapy, potentially overcoming the challenges of antigen-low escape mechanisms and offering a more effective long-term solution for leukaemia patients. This approach could pave the way for improved treatment options and better patient outcomes in the future.
Helena Bradbury, EMJ
Reference
Pham-Danis C et al. Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia. Cancer Cell. 2025;43(3):482-502.
