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

Jiqin Zhang (), Yongxian Hu, Jiaxuan Yang, Wei Li, Mingming Zhang, Qingcan Wang, Linjie Zhang, Guoqing Wei, Yue Tian, Kui Zhao, Ang Chen, Binghe Tan, Jiazhen Cui, Deqi Li, Yi Li, Yalei Qi, Dongrui Wang, Yuxuan Wu, Dali Li (), Bing Du (), Mingyao Liu () and He Huang ()
Additional contact information
Jiqin Zhang: East China Normal University
Yongxian Hu: Zhejiang University School of Medicine
Jiaxuan Yang: East China Normal University
Wei Li: BRL Medicine, Inc.
Mingming Zhang: Zhejiang University School of Medicine
Qingcan Wang: BRL Medicine, Inc.
Linjie Zhang: East China Normal University
Guoqing Wei: Zhejiang University School of Medicine
Yue Tian: East China Normal University
Kui Zhao: Zhejiang University
Ang Chen: East China Normal University
Binghe Tan: East China Normal University
Jiazhen Cui: Zhejiang University School of Medicine
Deqi Li: BRL Medicine, Inc.
Yi Li: Zhejiang University School of Medicine
Yalei Qi: East China Normal University
Dongrui Wang: Zhejiang University School of Medicine
Yuxuan Wu: East China Normal University
Dali Li: East China Normal University
Bing Du: East China Normal University
Mingyao Liu: East China Normal University
He Huang: Zhejiang University School of Medicine

Nature, 2022, vol. 609, issue 7926, 369-374

Abstract: Abstract Recently, chimeric antigen receptor (CAR)-T cell therapy has shown great promise in treating haematological malignancies1–7. However, CAR-T cell therapy currently has several limitations8–12. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05140-y

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