Chimeric antigen receptor-modified T cells strike back

Abstract

Chimeric antigen receptors (CARs) are engineered molecules designed to endow a polyclonal T-cell population with the ability to recognize tumor-associated surface antigens. In their simplest form, CARs comprise a targeting moiety in the form of a single-chain variable fragment from an antibody connected to various intracellular signaling domains allowing for T-cell activation. This powerful approach combines the specificity of an antibody with the cytotoxic ability of a T cell. There has been much excitement since early phase trials of CAR-T cells targeting CD19 expressed on B-cell malignancies demonstrated remarkable efficacy in inducing long-term, stable remissions in otherwise relapsed/refractory disease. Despite these successes, we have just begun to understand the intricacies of CAR biology with efforts underway to utilize this platform in the treatment of other, previously refractory malignancies. Challenges currently include identification of viable cancer targets, management strategies for potentially severe and irreversible toxicities and overcoming the immunosuppressive nature of the tumor microenvironment. This review will focus on basic CAR structure and function, previous success and new approaches aimed at the broader application of CAR-T-cell therapy.

Keywords: T-cell therapy; cellular immunotherapy; chimeric antigen receptor; clinical immunology; gene therapy.

Fig. 1.

The evolution of CARs. Early CARs were molecules composed of ectodomains from immunoglobulin V_H or V_L or from various receptors, fused with the TCR α or β chain. Modern CARs are composed of an extracellular antigen-binding domain usually derived from an immunoglobulin scFv, an extracellular spacer or ‘hinge’, a transmembrane domain and various ICDs required for T-cell activation.

Fig. 2.

Overview of CAR adoptive cell transfer. T cells are collected via apheresis, expanded ex vivo and genetically modified to express a desired CAR construct before they are infused back into the patient. Reproduced with permission of Annual Review of Medicine, Volume 65 Copyright © 2014 by Annual Reviews, http://www.annualreviews.org.