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

• Published in: International journal of molecular sciences Vol. 19; no. 1; p. 289
• Main Authors: Dörrie, Jan, Babalija, Lek, Hoyer, Stefanie, Gerer, Kerstin F, Schuler, Gerold, Heinzerling, Lucie, Schaft, Niels
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18-01-2018; MDPI
• Subjects: Adoptive transfer; Antigens; BRAF inhibitor; CAR-T cell; CD25 antigen; CD69 antigen; CD8 antigen; Cell activation; Chimeric antigen receptors; cobimetinib; dabrafenib; Immune checkpoint; Immune system; Immunotherapy; Inhibitors; kinase inhibitor; Lymphocytes; Lymphocytes T; MEK inhibitor; MEK inhibitors; Melanoma; T cell receptors; Targeted cancer therapy; trametinib; vemurafenib; trametinib; kinase inhibitor; immunotherapy; vemurafenib; BRAF inhibitor; melanoma; MEK inhibitor; cobimetinib; CAR-T cell; dabrafenib
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19010289

BRAF and MEK inhibitors (BRAFi/MEKi), the standard treatment for patients with BRAF
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.