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Review
. 2019 Mar 14;20(6):1283.
doi: 10.3390/ijms20061283.

Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells

Mohamed-Reda Benmebarek  1 , Clara Helke Karches  2 , Bruno Loureiro Cadilha  3 , Stefanie Lesch  4 , Stefan Endres  5 , Sebastian Kobold  6
Affiliations
Review

Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells

Mohamed-Reda Benmebarek et al. Int J Mol Sci. .

Abstract

Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor's individual components-scFv, spacer domain, and costimulatory domains-and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects.

Keywords: adoptive T cell therapy; cancer immunotherapy; chimeric antigen receptor.

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Conflict of interest statement

B.L.C., S.K. and S.E. are inventors of patent applications in the field of cellular therapies, however unrelated to the concepts presented here. S.K. and S.E. receive research support from TCR2 Inc., Boston, USA for work unrelated to the present manuscript.

Figures

Figure 1
Figure 1
A chimeric antigen receptor (CAR) is composed of several components, each of which contributes towards the proper activation, functionality, and persistence of CAR T cells. In addition to the CAR, T cell gene editing approaches can also augment functional potential.
Figure 2
Figure 2
CAR vs T cell receptor (TCR) T cell functionality: Time interval between synapse formation and disengagement following lysis is shorter for CAR T cells compared to TCR T cells. Signal strength during engagement is stronger in CAR T cells compared to TCR T cells. Quantified granzyme and perforin release during engagement was also comparable, despite the difference kinetics. Units are depicted relative to fold change. Granzyme and perforin release depicted in blue. Signal strength depicted in red. (Adapted from [51]).
Figure 3
Figure 3
CAR T cells mediate tumor killing via three axes: (1) Perforin and granzyme axis: Targeting antigen positive fraction. (2) Cytokine secretion: Stromal cell sensitization. (3) Fas and FasL axis: Targeting antigen-negative fraction.
Figure 4
Figure 4
CRISPR-based approaches for the genetic modification of CAR T cells. Gene disruption approaches have been shown to be effective for the silencing of inhibitory axis, and the development of universal CAR T cells. Red solid and dotted lines depict silencing or disruption of genes. Blue line depicts insertion of CAR.
See this image and copyright information in PMC

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