Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma |
| |
| Authors: | Akimasa Tomida Shigeki Yagyu Kayoko Nakamura Hiroshi Kubo Kumiko Yamashima Yozo Nakazawa Hajime Hosoi Tomoko Iehara |
| |
| Institution: | 1. Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan;2. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan;3. Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan;4. Center for Advanced Research of Gene and Cell Therapy in Shinshu University (CARS), Shinshu University School of Medicine, Matsumoto, Japan |
| |
| Abstract: | 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. |
| |
| Keywords: | CAR-T cell therapy chimeric antigen receptor GD2 MEK inhibitor neuroblastoma trametinib |
|
|
