Bispecific CAR T-cells for B-cell Malignancies

Introduction: Chimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell malignancies including acute lymphoblastic leukemia and non-Hodgkin lymphoma. All of the CARs approved for clinical use in treating B-cell malignancies are directed against a single antigen, CD19. Although the initial response rates are high, a significant number of patients relapse, with antigen loss being one proposed mechanism of treatment failure. Multi-targeted CAR T approaches are now being developed to overcome this limitation of currently approved CAR products. Areas covered: Here, we discuss the mechanism of antigen loss, various bispecific CAR T-cell constructs, and their efficacy and safety in the preclinical as well as clinical settings. Expert opinion: Although CD19 CAR T-cells have significantly improved response rates in relapsed/refractory B-cell malignancies, relapse remains a major barrier to long-term survival. Bispecific CAR T-cells offer an alternative approach to mitigate relapse associated with antigen loss. In B-cell malignancies, various bispecific CAR constructs are being studied. The CD19/CD20 and CD19/CD22 bispecific CARs have shown a favorable efficacy and safety profile in phase I trials. However, larger phase II studies and longer follow-ups are needed to better assess their efficacy and safety in patients with relapsed/refractory B-cell malignancies.