Challenges to chimeric antigen receptor (CAR)-T cell therapy for cancer

Abstract

Chimeric antigen receptor (CAR)-expressing T cells have demonstrated potent clinical efficacy in patients with B cell malignancies. However, the use of CAR-T cell therapy targeting other cancers has, in part, been limited by both the induction of antigen-specific toxicities targeting normal tissues expressing the target-antigen, and the extreme potency of CAR-T cell treatments resulting in life-threatening cytokine-release syndromes. Herein, we discuss toxicities associated with CAR-T cell therapy in the clinic. Further, we discuss potential clinical interventions to ameliorate these toxicities and the application of preclinical animal models to predict the clinical utility of CAR-T cell therapy.

Figure 1.. Chimeric Antigen Receptors.

Chimeric antigen receptors (CARs) combine antigen-recognizing variable regions (scFVs) from monoclonal antibodies (mAb) with intracellular T-cell signaling domains. First generation receptors utilized the CD3ζ chain of the T cell receptor (TCR) complex, while second and third generation receptors incorporate either one or two costimulatory singals, respectively, typically derived from B7 family molecules (CD28, ICOS) and/or the TNF superfamily (4–1BB, OX40, CD27). CARs are typically inserted into primary T cells via retroviral-mediated gene transfer.