Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma
2021
Disialoganglioside (GD2)-specific chimeric antigen receptor (CAR)-T cells (GD2-CAR-T cells) have been developed and tested in early clinical trials in patients with relapsed/refractory neuroblastoma. However, the effectiveness of immunotherapy using these cells is limited, and requires improvement. A combinatorial therapy with CAR-T cells and molecular targeted drugs could be a promising strategy to enhance the antitumor efficacy of CAR T-cell immunotherapy. Here, we generated GD2-CAR-T cells via piggyBac transposon (PB)-based gene transfer (PB-GD2-CAR-T cells), and analyzed the combinatorial effect of these cells and a mitogen-activated protein kinase kinase (MEK) inhibitor in vitro and in vivo on neuroblastoma. Trametinib, a MEK inhibitor, ameliorated the killing efficacy of PB-GD2-CAR-T cells in vitro, whereas a combinatorial treatment of the two exhibited superior antitumor efficacy in a murine xenograft model compared to that of PB-GD2-CAR-T cell monotherapy, regardless of the mutation status of MAPK pathway in tumor cells. The results presented here provide new insights into the feasibility of combinatorial treatment with CAR-T cells and MEK inhibitors in patients with neuroblastoma.
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