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Co-opting signalling molecules enables logic-gated control of CAR T cells

Author

Listed:
  • Aidan M. Tousley

    (Stanford University School of Medicine)

  • Maria Caterina Rotiroti

    (Stanford University School of Medicine)

  • Louai Labanieh

    (Stanford University
    Parker Institute for Cancer Immunotherapy)

  • Lea Wenting Rysavy

    (Stanford University School of Medicine)

  • Won-Ju Kim

    (Stanford University School of Medicine)

  • Caleb Lareau

    (Parker Institute for Cancer Immunotherapy
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Elena Sotillo

    (Stanford University School of Medicine)

  • Evan W. Weber

    (Parker Institute for Cancer Immunotherapy
    University of Pennsylvania)

  • Skyler P. Rietberg

    (Stanford University School of Medicine)

  • Guillermo Nicolas Dalton

    (Stanford University School of Medicine)

  • Yajie Yin

    (Parker Institute for Cancer Immunotherapy
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Dorota Klysz

    (Stanford University School of Medicine)

  • Peng Xu

    (Stanford University School of Medicine)

  • Eva L. Serna

    (Stanford University)

  • Alexander R. Dunn

    (Stanford University
    Stanford University School of Medicine
    Stanford University)

  • Ansuman T. Satpathy

    (Parker Institute for Cancer Immunotherapy
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Crystal L. Mackall

    (Stanford University School of Medicine
    Parker Institute for Cancer Immunotherapy
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Robbie G. Majzner

    (Stanford University School of Medicine
    Parker Institute for Cancer Immunotherapy
    Stanford University School of Medicine)

Abstract

Although chimeric antigen receptor (CAR) T cells have altered the treatment landscape for B cell malignancies, the risk of on-target, off-tumour toxicity has hampered their development for solid tumours because most target antigens are shared with normal cells1,2. Researchers have attempted to apply Boolean-logic gating to CAR T cells to prevent toxicity3–5; however, a truly safe and effective logic-gated CAR has remained elusive6. Here we describe an approach to CAR engineering in which we replace traditional CD3ζ domains with intracellular proximal T cell signalling molecules. We show that certain proximal signalling CARs, such as a ZAP-70 CAR, can activate T cells and eradicate tumours in vivo while bypassing upstream signalling proteins, including CD3ζ. The primary role of ZAP-70 is to phosphorylate LAT and SLP-76, which form a scaffold for signal propagation. We exploited the cooperative role of LAT and SLP-76 to engineer logic-gated intracellular network (LINK) CAR, a rapid and reversible Boolean-logic AND-gated CAR T cell platform that outperforms other systems in both efficacy and prevention of on-target, off-tumour toxicity. LINK CAR will expand the range of molecules that can be targeted with CAR T cells, and will enable these powerful therapeutic agents to be used for solid tumours and diverse diseases such as autoimmunity7 and fibrosis8. In addition, this work shows that the internal signalling machinery of cells can be repurposed into surface receptors, which could open new avenues for cellular engineering.

Suggested Citation

  • Aidan M. Tousley & Maria Caterina Rotiroti & Louai Labanieh & Lea Wenting Rysavy & Won-Ju Kim & Caleb Lareau & Elena Sotillo & Evan W. Weber & Skyler P. Rietberg & Guillermo Nicolas Dalton & Yajie Yin, 2023. "Co-opting signalling molecules enables logic-gated control of CAR T cells," Nature, Nature, vol. 615(7952), pages 507-516, March.
  • Handle: RePEc:nat:nature:v:615:y:2023:i:7952:d:10.1038_s41586-023-05778-2
    DOI: 10.1038/s41586-023-05778-2
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    Citations

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    Cited by:

    1. Shuhong Li & Licai Shi & Lijun Zhao & Qiaoru Guo & Jun Li & Ze-lin Liu & Zhi Guo & Yu J. Cao, 2024. "Split-design approach enhances the therapeutic efficacy of ligand-based CAR-T cells against multiple B-cell malignancies," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Shiyu Zuo & Chuo Li & Xiaolei Sun & Biping Deng & Yibing Zhang & Yajing Han & Zhuojun Ling & Jinlong Xu & Jiajia Duan & Zelin Wang & Xinjian Yu & Qinlong Zheng & Xiuwen Xu & Jiao Zong & Zhenglong Tian, 2024. "C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Pei Liu & Josquin Foiret & Yinglin Situ & Nisi Zhang & Aris J. Kare & Bo Wu & Marina N. Raie & Katherine W. Ferrara & Lei S. Qi, 2023. "Sonogenetic control of multiplexed genome regulation and base editing," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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