Adoptive T Cell Therapies: A Comparison of T Cell Receptors and Chimeric Antigen Receptors

Abstract

The tumor-killing properties of T cells provide tremendous opportunities to treat cancer. Adoptive T cell therapies have begun to harness this potential by endowing a functionally diverse repertoire of T cells with genetically modified, tumor-specific recognition receptors. Normally, this antigen recognition function is mediated by an αβ T cell receptor (TCR), but the dominant therapeutic forms currently in development are synthetic constructs called chimeric antigen receptors (CARs). While CAR-based adoptive cell therapies are already showing great promise, their basic mechanistic properties have been studied in less detail compared with those of αβ TCRs. In this review, we compare and contrast various features of TCRs versus CARs, with a goal of highlighting issues that need to be addressed to fully exploit the therapeutic potential of both.

Keywords: CAR; TCR; cell therapies; gene therapies; immunotherapy; receptors.

Figure 1. Structural Components of T Cell Receptor (TCR) and Chimeric Antigen Receptor (CAR) Signaling

(A) TCRs comprise an αβ heterodimer that binds to peptide major histocompatibility complex (pepMHC). (B) CARs are single-chain molecules that contain a single-chain variable fragment (scFv) recognition domain capable of binding to cell surface antigens. Incomplex with each TCR are CD3 subunits andacoreceptor (CD4 orCD8) associated with Lymphocyte-specific protein tyrosine kinase (Lck). CARs contain intracellular signaling domains from CD3ζ and a co-stimulatory molecule (typically CD28 or 4-1BB). Signaling is initiated by Lck-mediated phosphorylation of immuno-tyrosine activation motifs (ITAMs) within the cytoplasmic domains of CD3.

Figure 2. Common Signaling Domain Sequences Used in Chimeric Antigen Receptors (CARs)

(A) The CD3ζ cytoplasmic domain comprises three immuno-tyrosine activation motifs (ITAMs; in red) that become phosphorylated upon ligand engagement and serve as docking domains for downstream signaling molecules. (B) The CD28 cytoplasmic domain contains an ITAM-like sequence (red) and two proline-rich motifs (blue) that provide docking domains for recruitment of co-stimulatory signaling molecules. (C) The 4-1BB cytoplasmic domain contains two acidic motifs (blue) that provide sites for TRAF molecules to associate.