A culture method with berbamine, a plant alkaloid, enhances CAR-T cell efficacy through modulating cellular metabolism

  • Commun Biol. 2024 Jun 4;7(1):685. doi: 10.1038/s42003-024-06297-0.
Shin-Ichiro Takayanagi  #  1  2  3 ,  Sayaka Chuganji  #  4  5 ,  Masahiro Tanaka  5 ,  Bo Wang  5 ,  Saki Hasegawa  4  5 ,  Ken Fukumoto  4  5 ,  Nariaki Wasano  4 ,  Makoto Kakitani  4 ,  Nakaba Ochiai  4  5 ,  Yohei Kawai  5 ,  Tatsuki Ueda  5 ,  Akihiro Ishikawa  5 ,  Yuko Kurimoto  4 ,  Asami Fukui  4 ,  Sanae Kamibayashi  5 ,  Eri Imai  5 ,  Atsushi Kunisato  4 ,  Hajime Nozawa  4 ,  Shin Kaneko  6
Affiliations
  • 1. Kirin Central Research Institute, Kirin Holdings Company, Ltd., 26-1, Muraoka-Higashi 2, Fujisawa, Kanagawa, 251-8555, Japan. [email protected].
  • 2. Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. [email protected].
  • 3. Biomedical Science Research Laboratories 2, Research Division, Kyowa Kirin Co., Ltd., Tokyo, Japan. [email protected].
  • 4. Kirin Central Research Institute, Kirin Holdings Company, Ltd., 26-1, Muraoka-Higashi 2, Fujisawa, Kanagawa, 251-8555, Japan.
  • 5. Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
  • 6. Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. [email protected].
  • # Contributed equally.
PMID: 38834758 DOI: 10.1038/s42003-024-06297-0
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.

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