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Recent advances and discoveries in the mechanisms and functions of CAR T cells

Abstract

This Review discusses the major advances and changes made over the past 3 years to our understanding of chimeric antigen receptor (CAR) T cell efficacy and safety. Recently, the field has gained insight into how various molecular modules of the CAR influence signalling and function. We report on mechanisms of toxicity and resistance as well as novel engineering and pharmaceutical interventions to overcome these challenges. Looking forward, we discuss new targets and indications for CAR T cell therapy expected to reach the clinic in the next 1–2 years. We also consider some new studies that have implications for the future of CAR T cell therapies, including changes to manufacturing, allogeneic products and drug-regulatable CAR T cells.

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Fig. 1: Schematic of a basic second-generation CAR T cell.
Fig. 2: Current molecular understanding and therapeutic intervention of CAR T cell-induced cytokine release syndrome and neurotoxicity.
Fig. 3: Antigen-dependent and antigen-independent resistance.
Fig. 4: CAR T cell subsets with increased efficacy and universal CARs with interchangeable targets.

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Acknowledgements

M.V.M. is funded by the National Institutes of Health (NIH) (R01 CA238268, R01 CA252940), the Leukemia and Lymphoma Society, Stand Up to Cancer and the Damon Runyon Cancer Research Foundation. R.C.L. has been funded by NIH T32 GM007306 and is currently funded by NIH T32 AI007529.

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M.V.M. and R.C.L. researched the data for the article and selected the content, and otherwise contributed equally to writing the article and to review and/or editing of the manuscript before submission.

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Correspondence to Marcela V. Maus.

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M.V.M. and R.C.L. have intellectual property on certain chimeric antigen receptor (CAR) T cells and antibodies (not yet licensed). M.V.M. receives consulting income from several industry sponsors that market CAR T cell therapies, serves on several scientific advisory boards and has equity in TCR2 and Century Therapeutics.

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Glossary

Camelid antibodies

Antibodies generated from Camelidae mammals, which have two identical heavy chains and, compared with typical antibodies, are much smaller (15 kDa compared with 150 kDa) and lack a light chain.

Graft-versus-host disease

(GvHD). A condition that can occur after allogeneic transplant owing to donor cells recognizing the host as foreign, resulting in donor cell attack of the host body.

Leukapheresis

A procedure in which white blood cells are separated from the blood and the remaining cells are returned to the circulation.

Artificial antigen-presenting cells

(Artificial APCs). Synthetic versions of APCs that activate immune cells; in the context of chimeric antigen receptor (CAR) T cells, artificial APCs are engineered with T cell receptor (TCR) stimulation and co-stimulatory molecules to expand T cells ex vivo.

Transcription activator-like effector nucleases

(TALENs). DNA-binding domains fused to non-specific DNA-cleaving nucleases to target a specific sequence for gene alteration.

Hypomorphic mutation

An altered gene resulting in lower expression and/or activity of the gene product.

Tonic signalling

Ligand-independent constitutive signalling of a chimeric antigen receptor (CAR).

Activation-induced cell death

Programmed cell death caused by repeated stimulation of T cells that serves as a negative regulator of activation.

Maximum tolerated dose

The highest dose of treatment that does not cause intolerable side effects.

Suicide switches

Genetically encoded molecules included in a chimeric antigen receptor (CAR) vector that can be targeted to induce CAR T cell death.

Trogocytosis

A process where lymphocytes extract ligands from antigen-presenting cells and express them on their own surface.

Bispecific T cell engager

(BiTE). An artificial bispecific antibody made up of two single-chain variable fragments (scFvs) — one that recognizes a specific antigen and the other that binds CD3 on T cells, eliciting an activation response.

Amphiphilic

A description of a molecule containing both hydrophobic and hydrophilic regions.

Transposons

Genetic segments that can be translocated in the genome from one location to another by a DNA transposase.

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Larson, R.C., Maus, M.V. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer 21, 145–161 (2021). https://doi.org/10.1038/s41568-020-00323-z

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