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

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.

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

“…As described earlier, the use of immune checkpoint inhibitors in combination with a BRAF inhibitor + MEK inhibitor appears to be effective but is associated with a high rate of toxicity [ 194 ]. Other potential immune-targeted therapies undergoing preclinical investigation include adoptive T-cell therapy [ 171 , 248 , 249 ], dendritic cell vaccination [ 250 ], and combining BRAF inhibitor treatment with a toll-like receptor 7 agonist (e.g., imiquimod) [ 160 ].…”

Two cases of dabrafenib and trametinib therapy‐failed advanced melanoma successfully controlled by nivolumab monotherapy

“…Nivolumab, an anti-PD-1 Ab, significantly prolonged the survival in patients with metastatic melanoma, and is known to induce long-acting antitumor immune effects. 2 Because the release of tumor-specific antigen is necessary for the induction of the antitumor immune response, 4 DT before or after the administration of nivolumab may augment the immune response against melanoma. 4,5 Tumor-associated macrophages (TAM) create an immunosuppressive microenvironment together with other suppressor cells in the tumor-bearing host, and have been detected in various skin cancers including melanomas.…”

“…2 Because the release of tumor-specific antigen is necessary for the induction of the antitumor immune response, 4 DT before or after the administration of nivolumab may augment the immune response against melanoma. 4,5 Tumor-associated macrophages (TAM) create an immunosuppressive microenvironment together with other suppressor cells in the tumor-bearing host, and have been detected in various skin cancers including melanomas. 6 Moreover, as Gordon et al 7 reported, TAM in melanoma express PD-1, and the blockade of PD-ligand 1/PD-1 signaling induces M1-like responses, leading to an antitumor immune response in melanomas.…”

“…Nivolumab, an anti‐PD‐1 Ab, significantly prolonged the survival in patients with metastatic melanoma, and is known to induce long‐acting antitumor immune effects . Because the release of tumor‐specific antigen is necessary for the induction of the antitumor immune response, DT before or after the administration of nivolumab may augment the immune response against melanoma …”

The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

“…A special safety measurement to circumvent prolonged autoimmunity induced by an on-target/ off-tumor reaction of the CAR is the introduction of the CAR by mRNA electroporation (n = 5, 2.6%; Figure 4). We have previously demonstrated that transient transfection of T cells with CARs using mRNA electroporation might be an effective and safe tool in cancer immunotherapy [121,[216][217][218][219][220]. The electroporation procedure is based on complex physicochemical mechanisms leading to plasma membrane perforation upon application of electric fields allowing for subsequent entry of mRNA into the cytosol [221].…”