1. A culture method with berbamine, a plant alkaloid, enhances CAR-T cell efficacy through modulating cellular metabolism.
- Author
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Takayanagi, Shin-ichiro, Chuganji, Sayaka, Tanaka, Masahiro, Wang, Bo, Hasegawa, Saki, Fukumoto, Ken, Wasano, Nariaki, Kakitani, Makoto, Ochiai, Nakaba, Kawai, Yohei, Ueda, Tatsuki, Ishikawa, Akihiro, Kurimoto, Yuko, Fukui, Asami, Kamibayashi, Sanae, Imai, Eri, Kunisato, Atsushi, Nozawa, Hajime, and Kaneko, Shin
- Subjects
T cells ,CELL culture ,MITOGEN-activated protein kinases ,IMMUNOLOGIC memory ,METABOLISM ,ALKALOIDS ,CHIMERIC antigen receptors - Abstract
Memory T cells demonstrate superior in vivo persistence and antitumor efficacy. However, methods for manufacturing less differentiated T cells are not yet well-established. Here, we show that producing chimeric antigen receptor (CAR)-T cells using berbamine (BBM), a natural compound found in the Chinese herbal medicine Berberis amurensis, enhances the antitumor efficacy of CAR-T cells. BBM is identified through cell-based screening of chemical compounds using induced pluripotent stem cell-derived T cells, leading to improved viability with a memory T cell phenotype. Transcriptomics and metabolomics using stem cell memory T cells reveal that BBM broadly enhances lipid metabolism. Furthermore, the addition of BBM downregulates the phosphorylation of p38 mitogen-activated protein kinase and enhanced mitochondrial respiration. CD19-CAR-T cells cultured with BBM also extend the survival of leukaemia mouse models due to their superior in vivo persistence. This technology offers a straightforward approach to enhancing the antitumor efficacy of CAR-T cells. When used in CAR-T cell processing, the plant alkaloid berbamine prolongs the survival of leukemic animals by boosting CAR-T cell viability, memory phenotype, and persistence by modulating cellular metabolism, including mitochondrial respiration. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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