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Review
. 2023 Mar 15;21(1):197.
doi: 10.1186/s12967-023-04041-6.

Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility

Piotr Celichowski  1   2 , Marcello Turi  1   2   3 , Sandra Charvátová  1   2   3 , Dhwani Radhakrishnan  1   2   3 , Neda Feizi  4 , Zuzana Chyra  1   2 , Michal Šimíček  1   2 , Tomáš Jelínek  1   2 , Juli Rodriguez Bago  1   2 , Roman Hájek  1   2 , Matouš Hrdinka  5   6
Affiliations
Review

Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility

Piotr Celichowski et al. J Transl Med. .

Abstract

Cancer immunotherapies utilizing genetically engineered T cells have emerged as powerful personalized therapeutic agents showing dramatic preclinical and clinical results, particularly in hematological malignancies. Ectopically expressed chimeric antigen receptors (CARs) reprogram immune cells to target and eliminate cancer. However, CAR T cell therapy's success depends on the balance between effective anti-tumor activity and minimizing harmful side effects. To improve CAR T cell therapy outcomes and mitigate associated toxicities, scientists from different fields are cooperating in developing next-generation products using the latest molecular cell biology and synthetic biology tools and technologies. The immunotherapy field is rapidly evolving, with new approaches and strategies being reported at a fast pace. This comprehensive literature review aims to provide an up-to-date overview of the latest developments in controlling CAR T cell activity for improved safety, efficacy, and flexibility.

Keywords: CAR; Cancer; Cell therapy; Chimeric antigen receptor; Immunotherapy; Regulation; Synthetic; T cell.

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Conflict of interest statement

T.J. received honoraria from Amgen, BMS, Janssen, GSK, Takeda, Pfizer, Sanofi; and research funding from Sanofi, Janssen, Amgen. R.H. has had a consultant or advisory relationship with Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; has received honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; has received research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic overview of the various approaches developed to modulate CAR T cell activities as discussed in this review. Six broad categories are discussed: (1) Elimination of therapeutic cells, (2) Regulation of CAR gene expression, (3) Inducible CAR protein degradation, (4) Inducible formation of a functional CAR or inducible CAR disassembly, (5) Inhibitory CARs, and (6) Modular universal adaptor CAR platforms. CID, chemical inducer of dimerization
Fig. 2
Fig. 2
The action of suicide genes. A Internal suicide gene is an enzyme that changes a non-toxic drug to a toxic compound that triggers apoptosis. B Dimerization with a small drug that causes activation of apoptosis-triggering protein. CID, chemical inducer of dimerization. C Surface suicide receptor or ADCC target triggering apoptosis upon contact with an extracellular drug or antibody
Fig. 3
Fig. 3
An overview of strategies used for inducible control and modulation of CAR mRNA expression. TF, transcription factor
Fig. 4
Fig. 4
A schematic overview of strategies developed for inducible CAR receptor degradation. CARs with incorporated degradation domains might be degraded or protected against degradation by a small molecule drug. In other technologies, a CAR-inhibiting protein is co-expressed with CAR to regulate CAR function based on the presence or absence of a small molecule
Fig. 5
Fig. 5
Inducible formation of a functional CAR or inducible CAR disassembly. The CAR is split into two parts that associate (ON-switches) or dissociate (OFF-switches) upon activation by small molecule drugs. CID, chemical inducer of dimerization
Fig. 6
Fig. 6
Inhibitory CAR receptors. When co-expressed with conventional CARs, the inhibitory CARs prevent CAR T cells from killing normal cells with target antigen expression, thus increasing the specificity of CAR T cells
Fig. 7
Fig. 7
The schematic of two-component adaptor CAR platforms. The soluble adaptor or antigen recognition molecule (component 2) binds to the transmembrane receptor (component 1) at the surface of the engineered T cells to form a functional CAR activating T cell effector functions
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