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

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Trends

T cells engineered to express receptors for cancer antigens show great promise.

The receptors include conventional TCRs and CARs.

TCRs and CARs have distinct signaling properties and antigen sensitivities.

Adoptive T cell therapies provide an ultrasensitive, polyfunctional modality.

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.

Section snippets

The Rise of Adoptive T Cell Cancer Therapies

The success of adoptive T cell therapies, using genetically engineered receptors against cancer antigens, has recently gained the interest of biotechnology and pharmaceutical companies [1]. Much of the attention has focused on synthetic receptors now commonly referred to as CARs. CARs typically link an extracellular, antigen-recognition molecule comprising antibody domains (a single-chain Fv, scFv, containing the variable domains of the light and heavy chains; see Glossary), a stalk-like

TCR: Structure and Signaling

The TCR is an αβ heterodimer that binds to a short peptide bound to a product of the MHC. Each αβ subunit contains variable (V) and constant (C) region domains, and the latter is followed by a transmembrane region. Each V domain contains three loops, called complementarity-determining regions (CDR1, CDR2, and CDR3), which interact with the peptide (pep)MHC antigen. The conserved docking angle of the six CDRs over the pepMHC antigen is thought to confer maximal signaling capabilities and it

Chimeric Antigen Receptor: Structure and Signaling

Chimeric antigen receptors (CARs) represent a class of synthetic constructs typically comprising a single-chain antibody fragment (scFv, VH-linker-VL, or VL-linker-VH), an extracellular stalk (hinge) domain, a transmembrane domain, and one or more intracellular signaling domains 5, 39 (Figure 1). The scFv endows T cells with the ability to respond to cell surface antigens independent of MHC. The CAR format provides an opportunity to potentially exploit (or repurpose) many of the scFv that have

Sensitivity of TCRs and CARs: Impact of Affinity, Receptor Density, and Antigen Density

As emphasized above, based simply on their design, the mechanism by which CAR binding to its cognate antigen leads to T cell activation differs in substantial ways from the mechanism by which TCR binding leads to T cell activation. Even without consideration of co-stimulatory molecules (CD28 and 4-1BB), TCRs mediate activity through a complex of ten subunits that are poised to be triggered by low numbers of pepMHC antigens, and through the action of the coreceptors CD4 and CD8 11, 12, 13 (Box 1

Adoptive T Cell Therapy: Clinical Outcomes Using TCRs and CARs

Early clinical data from adoptive T cell trials using TCRs and CARs have demonstrated the tremendous potential of redirected T cells in the control of tumors. Some of the most exciting results have come from trials using CAR T cells against hematological cancers. As described in recent reviews 1, 3, 4, the variability in scFv fragments, co-stimulatory domains, and methods of gene transfer (such as retrovirus, lentivirus, or other newly developed techniques), have made it difficult to compare

Concluding Remarks

Adoptive T cell therapies using engineered receptors that bind to cancer antigens have received much attention due to early clinical successes. The two major formats of these receptors target different types of antigen. TCRs target the natural ligands for T cells: cancer-associated peptides bound to an MHC product. Optimization of these receptors for adoptive T cell therapies will typically require raising the affinity above the normal levels [92] to mediate the activities of both CD8 and CD4 T

Acknowledgments

We thank past and present members of the lab for their contributions over the years and, in particular, we thank Jennifer Stone and Adam Chervin for helpful discussions. This work was supported by NIH grants CA178844, CA187592, and CA180723.

Glossary

4-1BB
a co-stimulatory molecule (also known as CD137) expressed on the surface of T cells. 4-1BB promotes the expression of the antiapoptotic factors, such as BCL-2, BCL-XL, and BCL2A1.
CD3
a cell-surface molecule expressed on T cells. CD3 subunits associate with the T cell receptor αβ heterodimer and contain intracellular signaling motifs for T cell activation. Three CD3 heterodimers (CD3ɛγ, CD3ɛδ, and CD3ζζ) occur within each TCR/CD3 complex.
CD4
a coreceptor molecule expressed on the surface of

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