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Agliardi, Giulia; Liuzzi, Anna Rita; Hotblack, Alastair; De Feo, Donatella; Núñez, Nicolás; Stowe, Cassandra L; Friebel, Ekaterina; Nannini, Francesco; Rindlisbacher, Lukas; Roberts, Thomas A; Ramasawmy, Rajiv; Williams, Iwan P; Siow, Bernard M; Lythgoe, Mark F; Kalber, Tammy L; Quezada, Sergio A; Pule, Martin A; Tugues, Sonia; Straathof, Karin; Becher, Burkhard
Nature communications, 01/2021, Volume: 12, Issue: 1Journal Article
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.
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