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

Abstract

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.

Figure 1.. Mechanisms of CAR T cell -driven immunoediting in B-cell leukemia.

CAR T-cell therapies involve the use of genetically engineered T-cells expressing chimeric antigen receptor (CAR) which target B-cells surface markers such as CD19 (red) or CD22 (green). A. Focal mutations in the CD19 gene (orange stars) are known to result in antigen loss. Nonsense mutations lead to expression of non-functional truncated protein; missense mutations mediate antigen escape via retention of the misfolded protein in endoplasmic reticulum; splice site mutations cause deleterious alterations in splicing such as intron retention. B. Non-mutational mechanisms such as alternative splicing, epitope shielding, antigen downregulation, and lineage switching have also been shown to cause acquired resistance to CAR T-cells.