Antigen-Specific T-Cell Activation Independently of the MHC: Chimeric Antigen Receptor-Redirected T Cells

Abstract

Adoptive T-cell therapy has recently shown promise in initiating a lasting anti-tumor response with spectacular therapeutic success in some cases. Specific T-cell therapy, however, is limited since a number of cancer cells are not recognized by T cells due to various mechanisms including the limited availability of tumor-specific T cells and deficiencies in antigen processing or major histocompatibility complex (MHC) expression of cancer cells. To make adoptive cell therapy applicable for the broad variety of cancer entities, patient's T cells are engineered ex vivo with pre-defined specificity by a recombinant chimeric antigen receptor (CAR) which consists in the extracellular part of an antibody-derived domain for binding with a "tumor-associated antigen" and in the intracellular part of a T-cell receptor (TCR)-derived signaling moiety for T-cell activation. The specificity of CAR-mediated T-cell recognition is defined by the antibody domain, is independent of MHC presentation and can be extended to any target for which an antibody is available. We discuss the advantages and limitations of MHC-independent T-cell targeting by an engineered CAR in comparison to TCR modified T cells and the impact of the CAR activation threshold on redirected T-cell activation. Finally we review most significant progress recently made in early stage clinical trials to treat cancer.

Keywords: T-cell receptor; adoptive cell therapy; antibody; antigen-presenting cell; chimeric antigen receptor.

Figure 1

Modular composition of the chimeric antigen receptor (CAR) compared to the T-cell receptor (TCR). The TCR binds to cognate peptide-loaded MHC (pMHC) by the TCR α and β chains, forms the immunological synapse by clustering accessory components including CD3ζ and CD28, and initiates the downstream signaling pathway for T-cell activation through phosphorylation of the CD3ζ ITAM motives. The CAR, in contrast, is composed of one polypeptide chain; the extracellular single chain fragment of variable region (scFv) antibody domain binds to the target antigen in a MHC-independent fashion. Upon CAR clustering, the intracellular CD3ζ chain, with or without costimulation through members of the CD28 family, initiates the downstream signaling for T-cell activation. Co-receptors may modulate CAR activity. In contrast to a first generation (1°) CAR, second (2°), and third (3°) generation CARs harbor in addition one or more costimulatory moieties in their intracellular part.