fig4

Figure 4. Strategies to overcome resistance. (A) New combinations with CAR T-cell infusions include ibrutinib, lenalidomide, checkpoint inhibitors, and dasatinib with promising mechanisms of improving CAR T-cell function, expansion, durability, and safety; (B) Novel targets including new antigens of interest, and dual targeting CAR T-cell methods. Dual targeting methods include bispecific CAR T-cells, which include 2 different CARs targeting 2 antigens per T-cell, tandem CAR T-cells with 2 antigen targets on each CAR, and sequential including 2 CAR T-cells targeting different antigens given together or sequentially; (C) New generations of CAR T-cells such as “armored” CARs that can express a protein such as a cytokine that can help regulate the CAR T-cell and impact the TME. Allogenic CAR T-cells utilize healthy donor T-cells for an “off the shelf” option. They have the TCR and HLA1 receptors deleted to prevent complications with graft-versus-host-disease. CAR NK-cells can also utilize healthy donor cells and do not need to have TCR/HLA modification; however, they need additional stimulatory molecules to improve expansion and persistence. CAR: Chimeric antigen receptor; TME: tumor microenvironment; TCR: T-cell receptor; HLA1: human leukocyte antigen type 1; NK: natural killer; PD-1: programmed death-1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; PD-L1: programmed death ligand-1; CRS: cytokine release syndrome; ROR1: receptor tyrosine kinase like orphan receptor 1; FcµR: Fcµ receptor; BAFF-R: B-cell activating factor receptor; BCMA: B-cell maturation antigen.