Issues

Not all patients respond to CAR T-cell therapies, and the mechanisms behind this primary resistance are poorly understood. Singh, Lee, and colleagues found that deficits in death receptor signaling in acute lymphoblastic leukemia (ALL) cells can cause resistance to CD19-directed CAR T-cell therapy. Exposure to ALL cells in which death-receptor signaling was impaired caused CAR T-cell dysfunction that worsened with increasing exposure times. These dysfunctional CAR T cells exhibited a phenotype similar to that of exhausted T cells. Additionally, analysis of samples from clinical trials of CD19-directed CAR T cells showed that low expression of death receptor genes was associated with poorer response, demonstrating the clinical relevance of these findings. For details, please see the article by Singh, Lee, and colleagues on page 552.