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Navigating CAR-T cells through the solid-tumour microenvironment

Abstract

The adoptive transfer of T cells that are engineered to express chimeric antigen receptors (CARs) has shown remarkable success in treating B cell malignancies but only limited efficacy against other cancer types, especially solid tumours. Compared with haematological diseases, solid tumours present a unique set of challenges, including a lack of robustly expressed, tumour-exclusive antigen targets as well as highly immunosuppressive and metabolically challenging tumour microenvironments that limit treatment safety and efficacy. Here, we review protein- and cell-engineering strategies that seek to overcome these obstacles and produce next-generation T cells with enhanced tumour specificity and sustained effector function for the treatment of solid malignancies.

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Fig. 1: CARs are synthetic modular receptors with programmable antigen recognition.
Fig. 2: T cell-extrinsic factors limiting treatment efficacy against solid tumours.
Fig. 3: CAR-T cells face intrinsic and extrinsic metabolic challenges in the tumour microenvironment.
Fig. 4: CAR-T cell safety and control can be managed through genetic or pharmacological strategies.

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Acknowledgements

A.J.H. was supported by the Mark Foundation (grant to Y.Y.C.) and L.C.C. was supported by the National Science Foundation (grant to Y.Y.C.).

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Glossary

T cell exhaustion

An evolving term that broadly describes a state of T cell hypofunctionality, characterized by distinct epigenetic, metabolic and phenotypic signatures, as a consequence of chronic stimulation.

B cell aplasia

Depletion of healthy B cells in a patient receiving CAR-T cells targeting pan-B cell markers.

Mesothelial cells

Cells that line internal body cavities, including organs such as the heart and lungs.

Boolean AND-gate logic

A logical computation in which both condition ‘A’ AND condition ‘B’ must be met for the outcome to be true.

Boolean AND-NOT-gate

A logical computation in which condition ‘A’ must be true AND condition ‘B’ must NOT be true for the outcome to be true.

Bispecific T cell engager

(BiTE). A bispecific antibody consisting of a tumour-targeting antibody and a T cell-stimulating, anti-CD3 antibody.

Immunoreceptor tyrosine-based activation motifs

Conserved sequences found in the cytoplasmic region of CD3 T cell receptor chains that when phosphorylated serve as docking sites for downstream signalling molecules.

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Hou, A.J., Chen, L.C. & Chen, Y.Y. Navigating CAR-T cells through the solid-tumour microenvironment. Nat Rev Drug Discov 20, 531–550 (2021). https://doi.org/10.1038/s41573-021-00189-2

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