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The pharmacology of second-generation chimeric antigen receptors

Nature Reviews Drug Discovery volume 14, pages 499–509 (2015)Cite this article

Subjects

Key Points

  • T cell engineering is a novel therapeutic strategy designed to rapidly establish potent tumour immunity. Tumour antigen targeting and enhanced T cell functionality may be achieved through the expression of synthetic receptors for antigen, known as chimeric antigen receptors (CARs).

  • Second-generation CARs, which provide co-stimulatory signals in addition to initiating T cell activation, have shown impressive complete remissions in patients with B cell malignancies, especially acute lymphoblastic leukaemia and B cell lymphomas.

  • Co-stimulation is required for effective proliferation, persistence and function of CAR T cells.

  • CD28 and 4-1BB provide distinct, complementary co-stimulatory support to T cells, although their effect within CAR structures cannot be equated to that of the native receptors.

  • Both 28ζ and BBζ CARs show promising clinical results against B cell malignancies, with different tumour-killing kinetics. Inclusion of CD28 appears to mediate faster tumour reduction, whereas 4-1BB appears to promote T cell persistence.

  • The design and study of CARs is giving rise to the new field of immunopharmacology.

Abstract

Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging.

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Figure 1: Evolution of chimeric antigen receptors.
Figure 2: Second-generation anti-CD19 chimeric antigen receptors used in clinical trials to treat acute lymphoblastic leukaemia.

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Authors and Affiliations

  1. The Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA

    Sjoukje J. C. van der Stegen, Mohamad Hamieh & Michel Sadelain

  2. Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA

    Sjoukje J. C. van der Stegen, Mohamad Hamieh & Michel Sadelain

Authors
  1. Sjoukje J. C. van der Stegen
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  2. Mohamad Hamieh
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Correspondence to Michel Sadelain.

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M.S. is scientific co-founder of Juno Therapeutics. All other authors declare no conflict of interest.

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Glossary

T cell engineering

T cell isolation and modification intended to harness antigen specificity, proliferation, persistence and/or function.

Chimeric antigen receptor

(CAR). Fusion receptor combining antigen-recognition and T cell-activating properties. CARs consist of an antigen binding moiety (a single-chain variable fragment (scFv) or ligand), a hinge, a transmembrane domain and a cytoplasmic signalling domain, which includes a co-stimulatory domain in second-generation CARs.

First-generation CARs

Chimeric antigen receptors (CARs) with an endodomain consisting of the cytoplasmic signalling domain of CD3ζ or the Fcγ receptor.

Second generation CARs

Chimeric antigen receptors (CARs) that include a single co-stimulatory element within the endoplasmic domain in cis with the activating CD3ζ domain.

Anergy

Rapidly acquired state of T cell unresponsiveness occurring after suboptimal activation via the T cell receptor in the absence of co-stimulation or in the presence of co-inhibitory molecules.

Activation-induced cell death

(AICD). Apoptosis occurring following T cell activation.

Exhaustion

Progressive hyporesponsiveness developed by T cells after repeated exposure to antigen.

Single-chain variable fragment

(scFv). Fusion protein consisting of the variable fragments of the immunoglobulin heavy and light chains, connected by a glycine or serine linker.

Chimeric co-stimulatory receptor

Fusion molecule coupling antigen specificity to T cell co-stimulatory signalling, without activating domains.

Hinge

Also referred to as spacer domain; an extracellular component connecting the binding moiety to the transmembrane element.

Molecular remission

Complete remission and absence of disease based on PCR analysis.

Complete remission

Absence of disease based on imaging or biopsy analysis.

Severe cytokine release syndrome

A clinical syndrome comprising fever, hypotension, hypoxia and/or neurological symptoms, associated with cytokine release occurring following in vivo T cell activation.

Third-generation CARs

Chimeric antigen receptors (CARs) containing two co-stimulatory elements within the cytoplasmic domain in cis with the activating CD3ζ domain.

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van der Stegen, S., Hamieh, M. & Sadelain, M. The pharmacology of second-generation chimeric antigen receptors. Nat Rev Drug Discov 14, 499–509 (2015). https://doi.org/10.1038/nrd4597

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