BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism

Quanjun Yang; Xinting Zhu; Ping Huang; Chunyan Li; Leng Han; Yonglong Han; Run Gan; Bo Xin; Yixing Tu; Shumin Zhou; Ting Yuan; Juan Hao; Chunqiong Li; Li Zhang; Lei Shi; Cheng Guo

doi:10.1016/j.ymthe.2024.05.017

BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism

Mol Ther. 2024 May 11:S1525-0016(24)00319-8. doi: 10.1016/j.ymthe.2024.05.017. Online ahead of print.

Authors

Quanjun Yang¹, Xinting Zhu¹, Ping Huang², Chunyan Li³, Leng Han¹, Yonglong Han¹, Run Gan¹, Bo Xin¹, Yixing Tu¹, Shumin Zhou⁴, Ting Yuan⁵, Juan Hao⁶, Chunqiong Li⁷, Li Zhang⁷, Lei Shi⁸, Cheng Guo⁹

Affiliations

¹ Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
² Center for Chemical Glycobiology, Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
³ Shanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai JiaoTong University, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
⁴ Institution of Microsurgery on Extremities, Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
⁵ Department of Bone Oncology, Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
⁶ Department of Endocrinology, Shanghai Traditional Chinese Medicine-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, 230 Baoding Road, Shanghai 200082, China.
⁷ Chinese Institute for Brain Research, Beijing 102206, China.
⁸ Department of Oncology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan 430060, China. Electronic address: rm001276@whu.edu.cn.
⁹ Department of Pharmacy, Shanghai Sixth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China. Electronic address: guopharm@126.com.

PMID: 38734897
DOI: 10.1016/j.ymthe.2024.05.017

Abstract

Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cell treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and an increasing proportion of CAR-T cells in the peripheral circulation. BCKDK-KO CAR-T cell treatment resulted in shorter survival and a decreasing percentage of CAR-T cells in the peripheral circulation. In conclusion, BCKDK-engineered CAR-T cells exert a distinct phenotype for superior anticancer efficiency.

Keywords: BCKDK; branched chain amino acids; cancer metabolism; cancer microenvironment; chimeric antigen receptor; immunotherapy.