Chimeric antigen receptor T-cell therapy for solid tumors

Abstract

Chimeric antigen receptor (CAR) T cells are engineered constructs composed of synthetic receptors that direct T cells to surface antigens for subsequent elimination. Many CAR constructs are also manufactured with elements that augment T-cell persistence and activity. To date, CAR T cells have demonstrated tremendous success in eradicating hematological malignancies (e.g., CD19 CARs in leukemias). This success is not yet extrapolated to solid tumors, and the reasons for this are being actively investigated. Here in this mini-review, we discuss some of the key hurdles encountered by CAR T cells in the solid tumor microenvironment.

Figure 1

Building blocks of chimeric antigen receptor (CAR) T cell. The single chain (scFv) targeting moiety is taken from the antigen-binding domain of antibodies, fused to the CD3ζ transmembrane and intracellular signaling domains from the T-cell receptor complex; this is the first-generation CAR. Later, additional intracellular signaling domains were added for costimulatory signals, such as the CD28 and 41BB signaling domains, to yield second- and third-generation CARs.

Figure 2

Immunosuppressive tumor microenvironment. This diagram represents a simplified schema of the negative elements that barrage activated chimeric antigen receptor T cells as they navigate through the tumor landscape, thereby inactivating them. These barriers in solid tumors rapidly neutralize the antitumor effect.