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

Autor:	Agliardi G; Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Liuzzi AR; Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland., Hotblack A; Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., De Feo D; Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland., Núñez N; Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland., Stowe CL; Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Friebel E; Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland., Nannini F; Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Rindlisbacher L; Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland., Roberts TA; Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Ramasawmy R; Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Williams IP; Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Siow BM; Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK.; The Francis Crick Institute, NW1 1AT, London, UK., Lythgoe MF; Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Kalber TL; Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Quezada SA; Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Pule MA; Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK., Tugues S; Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland., Straathof K; Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. k.straathof@ucl.ac.uk.; UCL Great Ormond Street Institute of Child Health Biomedical Research Centre, WC1N 1EH, London, UK. k.straathof@ucl.ac.uk., Becher B; Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland. becher@immunology.uzh.ch.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2021 Jan 19; Vol. 12 (1), pp. 444. Date of Electronic Publication: 2021 Jan 19.
DOI:	10.1038/s41467-020-20599-x
Abstrakt:	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.
Databáze:	MEDLINE
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