Overcoming resistance to anti‐CD19 CAR T‐cell therapy in B‐cell malignancies

Abstract Anti‐CD19 chimeric antigen receptor (CAR) T‐cell therapy has rapidly changed current treatment pattern, providing a better option for individuals with primary refractory or relapsed B‐cell non‐Hodgkin lymphoma (r/r B‐NHL) and B‐cell acute lymphoblastic leukemia (r/r B‐ALL). However, despite the outstanding efficacy, a high relapse rate is still found in some B‐cell malignancies after anti‐CD19 CAR T‐cell therapy, which emerges as a main barrier for improving the overall response and long‐term outcomes. Understanding the resistance mechanism is crucial to improve current CAR T products, better incorporate them into the current therapy system and develop novel CAR approaches. Herein, we discuss the latest advances in understanding the mechanisms limiting efficacy of CAR T‐cell therapy, resulting in CD19 negative (CD19 − ) and CD19 positive (CD19 + ) relapses. We also provide a whole scenario of current potential strategies to overcome these barriers.