CAR T-cell immunotherapy of B-cell malignancy: the story so far

Abstract

Chimeric antigen receptor (CAR) T-cell immunotherapy has achieved unprecedented efficacy in the treatment of chemotherapy-resistant or refractory B-cell malignancies. Promising results from pivotal anti-CD19 CAR T-cell phase II trials have led to landmark approvals of two CD19-specific CAR T-cell products by the United States Food and Drug Administration and European Medicines Agency. However, several issues associated with CAR T-cell treatment remain unresolved, such as the management of severe toxicities and the frequent occurrence of both antigen-positive and antigen-negative relapse. Nonetheless, pre-clinical research is advancing at an unprecedented pace to develop innovative solutions to address these issues. Herein, we summarise recent clinical developments and outcomes of CD19-targeted CAR T-cell immunotherapy and discuss emerging strategies that may further improve the success, safety and broadened applicability of this approach.

Keywords: B-cell; CD19; chimeric antigen receptor; clinical trial; leukaemia; lymphoma.

Figure 1.

Evolution of CAR design over generations. First generation CARs consist of an antigen binding domain, usually an scFv, fused to a CD3ζ activation domain. Second generation CARs contain an additional intracellular costimulatory domain, usually CD28 or 4-1BB (CD137). Third generation CARs combine two or more costimulatory domains. CAR, chimeric antigen receptor.