In a syngeneic GBM mouse model, Agliardi and Liuzzi et al. showed a single, local IL-12:Fc dose combined with CAR T cells targeting a common GBM EGFR variant resulted in effective control of late-stage, orthotopic tumors. CAR T cells alone were only effective against early-stage tumors. Compared to CAR T cell monotherapy, adding one i.t. IL-12 dose reprogrammed cells in the TME, resulting in greater numbers of CD4+ T cells, increased IFNγ, and decreased LAG3/PD-1 expression in CD4+ and CD8+ T cells, and in activated myeloid cells. Local IL-12 had minimal systemic effects, suggesting it may be an effective clinical adjuvant.
Contributed by Katherine Turner
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.
Author Info: (1) Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (2) Institute of Experimental Immunology, Universi
Author Info: (1) Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (2) Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland. (3) Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (4) Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland. (5) Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland. (6) Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (7) Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland. (8) Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (9) Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland. (10) Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (11) Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (12) Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (13) 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. (14) Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (15) Centre for Advanced Biomedical Imaging (CABI), University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (16) Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (17) Research Department of Hematology, Cancer Institute, University College London, Paul O'Gorman Building, WC1E 6DD, London, UK. (18) Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland. (19) 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. (20) Institute of Experimental Immunology, University of Zurich, 8057, Zurich, Switzerland. becher@immunology.uzh.ch.
