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