ganglioside--gd2 and trametinib

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. Combined 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 through piggyBac transposon (PB)-based gene transfer (PB-GD2-CAR-T cells), and analyzed the combined effect of these cells and a 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 combined treatment of the two showed superior antitumor efficacy in a murine xenograft model compared to that of PB-GD2-CAR-T cell monotherapy, regardless of the mutation status of the MAPK pathway in tumor cells. The results presented here provide new insights into the feasibility of combined treatment with CAR-T cells and MEK inhibitors in patients with neuroblastoma.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Combined Modality Therapy; Coumarins; DNA Transposable Elements; Drug Resistance, Neoplasm; Female; Gangliosides; Genetic Therapy; Humans; Immunotherapy, Adoptive; Mice; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasm Recurrence, Local; Neuroblastoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; ras Proteins; Receptors, Chimeric Antigen; T-Lymphocytes; Xenograft Model Antitumor Assays