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

Giulia Agliardi, Anna Rita Liuzzi, Alastair Hotblack, Donatella Feo, Nicolás Núñez, Cassandra L. Stowe, Ekaterina Friebel, Francesco Nannini, Lukas Rindlisbacher, Thomas A. Roberts, Rajiv Ramasawmy, Iwan P. Williams, Bernard M. Siow, Mark F. Lythgoe, Tammy L. Kalber, Sergio A. Quezada, Martin A. Pule, Sonia Tugues, Karin Straathof () and Burkhard Becher ()
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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
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
Burkhard Becher: University of Zurich

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20599-x

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