CAR-T cell Therapies for B-cell Lymphoid Malignancies: Identifying Targets Beyond CD19

Chimeric antigen receptors (CARs) are synthetic engineered receptors with an antigen recognition domain derived from a high-specificity monoclonal antibody that can target surface molecules on tumor cells. T cells are genetically engineered to express CARs, thereby harnessing the antigen-recognition ability of antibodies and effector function of T cells. Target surface molecule selection is crucial for manufacturing CARs. Ideally, a target surface molecule should be restricted to tumor cells and minimally expressed or absent on normal tissues. Different CD19-targeted CAR-T cell therapies have been approved for the treatment of B-cell lymphoid malignancies that are refractory to other therapies, including indolent and aggressive B-cell non-Hodgkin lymphomas (NHL) and B-cell acute lymphoblastic leukemia (BALL). Despite impressive results, many patients with aggressive and refractory B-cell malignancies do not respond to or relapse after CD19 CAR-T cell therapies. Thus, several additional strategies are currently being evaluated to overcome these limitations. This review discusses studies on other promising CAR-T cell targets, including CD20, CD22, BAFF-R, ROR1, CD70, BCR complex, kappa/lambda light chains, multitargeted CAR-T cells, and combinations of CAR-T cell therapy with different drugs.