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Peer-reviewedCC BY 4.0Molecular Therapy Advances

A dual-switch safety system enables safety controllability and high-efficiency enrichment for T cell immunotherapy

  • Hongtao Liu1
  • Huimin Wang2
  • Bo Hou3
  • Wenxin Zhou1
  • Hanfei Zhu4
  • Xin Lin1,2,5
  • Jiasheng Wang1
5 affiliations
  1. 1Changping Laboratory, Yard 28, Science Park Road, Changping District, Beijing 102206, China
  2. 2School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China
  3. 3Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
  4. 4Yifei (Hangzhou) Bio-tech Co., Ltd, Hangzhou 311305, China
  5. 5Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 10084, China
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Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved durable and complete responses in a substantial proportion of patients with B cell malignancies. However, during CAR-T cell therapy, the occurrence of adverse events—including on-target/off-tumor toxicity against healthy tissues, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and the risk of T cell malignancies arising from random genomic integration of viral vectors—significantly threatens patient safety. In this study, we developed a novel truncated HER2 (tHER2)-herpes simplex virus thymidine kinase (HSVTK) dual-switch safety system and site-specifically integrated it into the PDCD1 locus using a Cas12a/adeno-associated virus (AAV)-mediated delivery platform. Importantly, this dual-switch system enables efficient magnetic bead-based enrichment of tHER2-HSVTK (tHER2-TK)-positive T cells, allows tunable modulation of engineered T cell persistence through Herceptin or the small-molecule drug ganciclovir (GCV), and also provides a highly effective purification method before infusion. Collectively, these features enhance safety without compromising therapeutic efficacy, facilitating the development of safer and more controllable engineered T cell immunotherapies.

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Cite

BibTeXRIS
BibTeX
@article{liu2026dualswitch,
  title = {{A dual-switch safety system enables safety controllability and high-efficiency enrichment for T cell immunotherapy}},
  author = {Hongtao Liu and Huimin Wang and Bo Hou and Wenxin Zhou and Hanfei Zhu and Xin Lin and Jiasheng Wang},
  journal = {Molecular Therapy Advances},
  year = {2026},
  month = oct,
  doi = {10.1016/j.omta.2026.201865},
  url = {https://doi.org/10.1016/j.omta.2026.201865},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A dual-switch safety system enables safety controllability and high-efficiency enrichment for T cell immunotherapy
AU  - Hongtao Liu
AU  - Huimin Wang
AU  - Bo Hou
AU  - Wenxin Zhou
AU  - Hanfei Zhu
AU  - Xin Lin
AU  - Jiasheng Wang
PY  - 2026
DA  - 2026/10/14
JO  - Molecular Therapy Advances
DO  - 10.1016/j.omta.2026.201865
UR  - https://doi.org/10.1016/j.omta.2026.201865
AB  - Chimeric antigen receptor (CAR) T cell therapy has achieved durable and complete responses in a substantial proportion of patients with B cell malignancies. However, during CAR-T cell therapy, the occurrence of adverse events—including on-target/off-tumor toxicity against healthy tissues, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and the risk of T cell malignancies arising from random genomic integration of viral vectors—significantly threatens patient safety. In this study, we developed a novel truncated HER2 (tHER2)-herpes simplex virus thymidine kinase (HSVTK) dual-switch safety system and site-specifically integrated it into the PDCD1 locus using a Cas12a/adeno-associated virus (AAV)-mediated delivery platform. Importantly, this dual-switch system enables efficient magnetic bead-based enrichment of tHER2-HSVTK (tHER2-TK)-positive T cells, allows tunable modulation of engineered T cell persistence through Herceptin or the small-molecule drug ganciclovir (GCV), and also provides a highly effective purification method before infusion. Collectively, these features enhance safety without compromising therapeutic efficacy, facilitating the development of safer and more controllable engineered T cell immunotherapies.
SN  - 3117-387X
ER  -