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Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma

Author

Listed:
  • Giulia Agliardi

    (University College London)

  • Anna Rita Liuzzi

    (University of Zurich)

  • Alastair Hotblack

    (University College London)

  • Donatella Feo

    (University of Zurich)

  • Nicolás Núñez

    (University of Zurich)

  • Cassandra L. Stowe

    (University College London)

  • Ekaterina Friebel

    (University of Zurich)

  • Francesco Nannini

    (University College London)

  • Lukas Rindlisbacher

    (University of Zurich)

  • Thomas A. Roberts

    (University College London)

  • Rajiv Ramasawmy

    (University College London)

  • Iwan P. Williams

    (University College London)

  • Bernard M. Siow

    (University College London
    The Francis Crick Institute)

  • Mark F. Lythgoe

    (University College London)

  • Tammy L. Kalber

    (University College London)

  • Sergio A. Quezada

    (University College London)

  • Martin A. Pule

    (University College London)

  • Sonia Tugues

    (University of Zurich)

  • Karin Straathof

    (University College London
    UCL Great Ormond Street Institute of Child Health Biomedical Research Centre)

  • Burkhard Becher

    (University of Zurich)

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4+ T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.

Suggested Citation

  • Giulia Agliardi & Anna Rita Liuzzi & Alastair Hotblack & Donatella Feo & Nicolás Núñez & Cassandra L. Stowe & Ekaterina Friebel & Francesco Nannini & Lukas Rindlisbacher & Thomas A. Roberts & Rajiv Ra, 2021. "Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20599-x
    DOI: 10.1038/s41467-020-20599-x
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    Cited by:

    1. Verena Turco & Kira Pfleiderer & Jessica Hunger & Natalie K. Horvat & Kianush Karimian-Jazi & Katharina Schregel & Manuel Fischer & Gianluca Brugnara & Kristine Jähne & Volker Sturm & Yannik Streibel , 2023. "T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Songlei Zhou & Yukun Huang & Yu Chen & Yipu Liu & Laozhi Xie & Yang You & Shiqiang Tong & Jianpei Xu & Gan Jiang & Qingxiang Song & Ni Mei & Fenfen Ma & Xiaoling Gao & Hongzhuan Chen & Jun Chen, 2023. "Reprogramming systemic and local immune function to empower immunotherapy against glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Yun Chang & Xuechao Cai & Ramizah Syahirah & Yuxing Yao & Yang Xu & Gyuhyung Jin & Vijesh J. Bhute & Sandra Torregrosa-Allen & Bennett D. Elzey & You-Yeon Won & Qing Deng & Xiaojun Lance Lian & Xiaogu, 2023. "CAR-neutrophil mediated delivery of tumor-microenvironment responsive nanodrugs for glioblastoma chemo-immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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