Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma
Giulia Agliardi, Anna Rita Liuzzi, Alastair Hotblack, Donatella De Feo, Nicolás Gonzalo Núñez, Cassandra Stowe, Ekaterina Friebel, Francesco Nannini, Lukas Rindlisbacher, Thomas A. Roberts, Rajiv Ramasawmy, Iwan P. Williams, Bernard Siow, Mark F. Lythgoe, Tammy L. Kalber, Sergio A. Quezada, Martin Pulé, Sònia Tugues, Karin Straathof, Burkhard Becher
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.