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.

Fig. 1 |. Limitations to durable remissions after CAR T cell therapy.

This figure summarizes several different limitations to achieving a durable remission with chimeric antigen receptor (CAR) T cell therapy. First, CAR T cell failures have several causes: for some patients, the CAR T cell product cannot be successfully manufactured or the generated CAR T cells do not expand sufficiently (either during manufacturing in vitro or after administration in vivo); in other patients, the problem of limited persistence in vivo is a potential mechanism underlying disease relapse. Second, antigen modulation — depicted by the loss or downregulation of CD19 and/or CD22 on malignant B cells — enables antigen escape as a mechanism of resistance to CAR T cell therapy, which can also be a problem in non-B cell malignancies, including solid tumours. Third, the characteristic toxicities of CAR T cell therapy — primarily severe cytokine-release syndrome (CRS) and/or neurotoxicity — can be fatal, thus abolishing the potential for therapeutic benefit in a small proportion of patients. Furthermore, data on the effect of therapeutic interventions for CRS on the durability of CAR remission remain unknown. Finally, unmet needs include some disease contexts that are a focus for ongoing research efforts to optimize the clinical utility of CAR T cell therapies. For example, although anti-CD19 CAR T cells can provide substantial benefit for adults with lymphoma, the complete remission rates are lower than those achieved in patients with leukaemia. Additionally, the outcomes of CAR T cell therapy in paediatric patients with lymphoma and in patients with central nervous system (CNS) involvement remain an area of ongoing investigation. Notably, such therapies currently have limited efficacy in patients with solid tumours, and approaches to optimize response are being explored.