Mechanisms of resistance to CAR T cell therapy

Abstract

The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma — the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.The development of chimeric antigen receptor (CAR) T cell therapy is an important advance in the treatment of cancer. Herein, the authors outline the key limitations of CAR T cell therapy, with a focus on mechanisms of resistance, and discuss strategies to improve the efficacy and broaden the applicability of this promising therapeutic approach.Key pointsChimeric antigen receptor (CAR) T cell immunotherapy is a highly effective form of adoptive cell therapy, as demonstrated by the remission rates in patients with B cell acute lymphoblastic leukaemia or large B cell lymphoma, which have supported FDA approvals.A complete understanding of the limitations of CAR T cell therapy will help to identify crucial areas requiring further research to improve patient outcomes.Factors that can preclude durable remissions following CAR T cell therapy include CAR T cell manufacturing issues, limited CAR T cell expansion and/or persistence, various resistance mechanisms and toxicities.Various intuitive strategies to overcome these obstacles are being investigated in order to optimize this unique therapeutic strategy and expand the indications for treatment.