Open AccessInhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma
Author(s) -
Tomida Akimasa,
Yagyu Shigeki,
Nakamura Kayoko,
Kubo Hiroshi,
Yamashima Kumiko,
Nakazawa Yozo,
Hosoi Hajime,
Iehara Tomoko
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15074
Subject(s) - chimeric antigen receptor , neuroblastoma , immunotherapy , cancer research , in vitro , in vivo , antigen , mek inhibitor , pharmacology , medicine , mapk/erk pathway , immunology , chemistry , biology , cell culture , immune system , signal transduction , microbiology and biotechnology , biochemistry , genetics
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.