Upregulation of the TCA Cycle and Oxidative Phosphorylation Enhances the Fitness of CD99 CAR-T Cells Under Dynamic Cultivation
Jiaxuan Zhao, Youyong Wang, Yixuan Wang, Ge Dong, Han Wu, Yeting Cui, Lixing Gu, Fenfang Zhao, Guanlin Zhao, Jinyu Kang, Qian Zhang, Nan Liu, Ning Wang, Xiao Sun, Yao Xu, Tongcun Zhang, Jiangzhou Shi
TL;DR
Dynamic cultivation using a wave bioreactor improves CAR-T cell function by enhancing their metabolism and memory-like properties.
Contribution
This study reveals that dynamic cultivation promotes mitochondrial metabolic reprogramming in CD99 CAR-T cells.
Findings
Wave bioreactor-cultured CAR-T cells show faster proliferation and stronger cytotoxicity.
These cells retain enhanced function and display reduced immune checkpoint molecule expression.
Metabolomic profiling shows increased TCA cycle activity and oxidative phosphorylation.
Abstract
The manufacturing process contributes significantly to the proliferation, metabolic state, and functional persistence of chimeric antigen receptor (CAR)-T cells. However, how different culture systems regulate CAR-T cell metabolism and thereby influence their long-term antitumor activity remains poorly understood. In this study, we compared dynamic cultivation using a wave bioreactor with static expansion systems (gas-permeable and conventional T-flasks) for the production of CD99-specific CAR-T cells. CAR-T cells expanded by the wave bioreactor exhibited faster proliferation and stronger cytotoxicity during culture. Upon repeated antigen stimulation, they retained these enhanced functional properties and showed the reduced expression of immune checkpoint molecules, preferentially preserved memory-like subsets, and displayed transcriptional features consistent with memory maintenance…
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Taxonomy
TopicsCAR-T cell therapy research · Viral Infectious Diseases and Gene Expression in Insects · Monoclonal and Polyclonal Antibodies Research