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Int. J. Mol. Sci. 2018, 19(1), 289; https://doi.org/10.3390/ijms19010289

BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy

1
Department of Dermatology, Universitätsklinikum Erlangen and Faculty of Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91052 Erlangen, Germany
2
Department of Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 21 December 2017 / Revised: 12 January 2018 / Accepted: 17 January 2018 / Published: 18 January 2018
(This article belongs to the Special Issue Chimeric Antigen Receptor (CAR) T Cell Therapy)
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Abstract

BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAFV600 mutated melanoma, are currently explored in combination with various immunotherapies, notably checkpoint inhibitors and adoptive transfer of receptor-transfected T cells. Since two BRAFi/MEKi combinations with similar efficacy are approved, potential differences in their effects on immune cells would enable a rational choice for triple therapies. Therefore, we characterized the influence of the clinically approved BRAFi/MEKi combinations dabrafenib (Dabra) and trametinib (Tram) vs. vemurafenib (Vem) and cobimetinib (Cobi) on the activation and functionality of chimeric antigen receptor (CAR)-transfected T cells. We co-cultured CAR-transfected CD8+ T cells and target cells with clinically relevant concentrations of the inhibitors and determined the antigen-induced cytokine secretion. All BRAFi/MEKi reduced this release as single agents, with Dabra having the mildest inhibitory effect, and Dabra + Tram having a clearly milder inhibitory effect than Vem + Cobi. A similar picture was observed for the upregulation of the activation markers CD25 and CD69 on CAR-transfected T cells after antigen-specific stimulation. Most importantly, the cytolytic capacity of the CAR-T cells was significantly inhibited by Cobi and Vem + Cobi, whereas the other kinase inhibitors showed no effect. Therefore, the combination Dabra + Tram would be more suitable for combining with T-cell-based immunotherapy than Vem + Cobi. View Full-Text
Keywords: BRAF inhibitor; MEK inhibitor; kinase inhibitor; CAR-T cell; dabrafenib; trametinib; vemurafenib; cobimetinib; melanoma; immunotherapy BRAF inhibitor; MEK inhibitor; kinase inhibitor; CAR-T cell; dabrafenib; trametinib; vemurafenib; cobimetinib; melanoma; immunotherapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Dörrie, J.; Babalija, L.; Hoyer, S.; Gerer, K.F.; Schuler, G.; Heinzerling, L.; Schaft, N. BRAF and MEK Inhibitors Influence the Function of Reprogrammed T Cells: Consequences for Adoptive T-Cell Therapy. Int. J. Mol. Sci. 2018, 19, 289.

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