Escape From ALL-CARTaz: Leukemia Immunoediting in the Age of Chimeric Antigen Receptors

: Chimeric antigen receptor (CAR) T-cell therapy has been transformative for the treatment of B-cell malignancies, with CD19- and CD22-directed CARs being prime examples. However, immunoediting and ensuing antigen loss remain the major obstacles to curative therapy in up to 25% of patients. For example, to achieve the CD19-negative phenotype, malignant cells can pick from a broad array of mechanisms, including focal loss-of-function mutations, dysregulated trafficking to the cell surface, alternative splicing, and lineage switching. In other cases, where resistance is mediated by insufficient antigen density, trogocytosis has been proposed as a possible underlying mechanism. To overcome these barriers, compensatory strategies will be needed, which could include using combinatorial CARs, harnessing epitope spreading, and targeting tumor neoantigens.