fig3

Figure 3. Resistance mechanisms. (A) Tumor-specific mechanisms are mostly due to selective pressure and include (1) proliferation of existing antigen-negative clones; (2) development of new genetic mutations within the antigen gene locus, loss of heterogeneity, or alternative splicing; (3) lineage switching, whereas the primary neoplastic cell becomes another type of cell (i.e., from lymphoid to myeloid); and (4) trogocytosis where the antigen of interest transfers to the CAR T-cell, leading to CAR T-cells killing each other (“fratricide”), and proliferation of the antigen-negative neoplastic cells; (B) CAR T-specific mechanisms include having CAR T-cells that have exhaustion phenotypes (i.e., expression of PD-1, LAG-3), which leads to impaired expansion, cytotoxicity, and persistence; (C) TME-specific mechanisms are due to immunosuppressive cells, inhibitory cytokines, and vesicles that protect CLL cells and cause impaired CAR T-cell function. CAR: Chimeric antigen receptor; PD-1: programmed death-1; LAG-3: lymphocyte-activation gene 3; TME: tumor microenvironment; CLL: chronic lymphocytic leukemia; LOH: loss of heterogeneity; PD-L1: program death ligand 1; CAF: cancer-associated fibroblast; MSCs: mesenchymal stromal cells; NLCs: nurse-like cells; TAMs: tumor-associated macrophages; MDSCs: monocyte-derived suppressor cells.