| Autor: |
Kentaro Tanaka, Kenji Chamoto, Sho Saeki, Ryusuke Hatae, Yuki Ikematsu, Kazuko Sakai, Nobuhisa Ando, Kazuhiro Sonomura, Shinsuke Kojima, Masanori Taketsuna, Young Hak Kim, Hironori Yoshida, Hiroaki Ozasa, Yuichi Sakamori, Tomoko Hirano, Fumihiko Matsuda, Toyohiro Hirai, Kazuto Nishio, Takuro Sakagami, Masanori Fukushima, Yoichi Nakanishi, Tasuku Honjo, Isamu Okamoto |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Science translational medicine. 14(675) |
| ISSN: |
1946-6242 |
| Popis: |
Despite the success of cancer immunotherapies such as programmed cell death–1 (PD-1) and PD-1 ligand 1 (PD-L1) inhibitors, patients often develop resistance. New combination therapies with PD-1/PD-L1 inhibitors are needed to overcome this issue. Bezafibrate, a ligand of peroxisome proliferator–activated receptor–γ coactivator 1α/peroxisome proliferator–activated receptor complexes, has shown a synergistic antitumor effect with PD-1 blockade in mice that is mediated by activation of mitochondria in T cells. We have therefore now performed a phase 1 trial (UMIN000017854) of bezafibrate with nivolumab in previously treated patients with advanced non–small cell lung cancer. The primary end point was the percentage of patients who experience dose-limiting toxicity, and this combination regimen was found to be well tolerated. Preplanned comprehensive analysis of plasma metabolites and gene expression in peripheral cytotoxic T cells indicated that bezafibrate promoted T cell function through up-regulation of mitochondrial metabolism including fatty acid oxidation and may thereby have prolonged the duration of response. This combination strategy targeting T cell metabolism thus has the potential to maintain antitumor activity of immune checkpoint inhibitors and warrants further validation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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