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

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Jan Dörrie ; Lek Babalija ; Stefanie Hoyer ; Kerstin F. Gerer ; Gerold Schuler ; Lucie Heinzerling ; Niels Schaft (2018)
  • Publisher: MDPI AG
  • Journal: International Journal of Molecular Sciences, volume 19, issue 1 (issn: 1422-0067, eissn: 1422-0067)
  • Related identifiers: pmc: PMC5796234, doi: 10.3390/ijms19010289
  • Subject: Chemistry | BRAF inhibitor | QD1-999 | vemurafenib | melanoma | cobimetinib | Article | QH301-705.5 | trametinib | kinase inhibitor | CAR-T cell | immunotherapy | MEK inhibitor | dabrafenib | Biology (General)

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.
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