Non-viral, specifically targeted CAR-T cells achieve high safety and efficacy in B-NHL

作者：Zhang, Jiqin; Hu, Yongxian; Yang, Jiaxuan; Li, Wei; Zhang, Mingming; Wang, Qingcan; Zhang, Linjie; Wei, Guoqing; Tian, Yue; Zhao, Kui; Chen, Ang; Tan, Binghe; Cui, Jiazhen; Li, Deqi; Li, Yi; Qi, Yalei; Wang, Dongrui; Wu, Yuxuan; Li, Dali; Du, Bing; Liu, Mingyao; Huang, He

来源：Nature, 2022, 609(7926): 369-+.

DOI：10.1038/s41586-022-05140-y

• CHIMERIC ANTIGEN RECEPTOR
• SLEEPING-BEAUTY
• IMMUNOTHERAPY
• THERAPY

Recently, chimeric antigen receptor (CAR)-T cell therapy has shown great promise in treating haematological malignancies(1-7). However, CAR-T cell therapy currently has several limitations(8-12). Here we successfully developed a two-in-one approach to generate non-viral, gene-specific targeted CAR-T cells through CRISPR-Cas9. Using the optimized protocol, we demonstrated feasibility in a preclinical study by inserting an anti-CD19 CAR cassette into the AAVS1 safe-harbour locus. Furthermore, an innovative type of anti-CD19 CAR-T cell with PD1 integration was developed and showed superior ability to eradicate tumour cells in xenograft models. In adoptive therapy for relapsed/refractory aggressive B cell non-Hodgkin lymphoma (ClinicalTrials.gov, NCT04213469), we observed a high rate (87.5%) of complete remission and durable responses without serious adverse events in eight patients. Notably, these enhanced CAR-T cells were effective even at a low infusion dose and with a low percentage of CAR(+) cells. Single-cell analysis showed that the electroporation method resulted in a high percentage of memory T cells in infusion products, and PD1 interference enhanced anti-tumour immune functions, further validating the advantages of non-viral, PD1-integrated CAR-T cells. Collectively, our results demonstrate the high safety and efficacy of non-viral, gene-specific integrated CAR-T cells, thus providing an innovative technology for CAR-T cell therapy.

• 单位
  浙江大学