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

Giulia Agliardi,Thomas A Roberts,Bernard Siow ,Mark F Lythgoe,Rajiv Ramasawmy,I P Williams ,Anna Rita Liuzzi,Alastair Hotblack,Nicolás Gonzalo Núñez ,Sergio A Quezada,Martin Pulé ,Francesco Nannini,Ekaterina Friebel,Cassandra Stowe ,Karin Straathof,Tammy L Kalber,Donatella De Feo,Sònia Tugues ,Lukas Rindlisbacher,Burkhard Becher

doi:10.1038/s41467-020-20599-x

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.

Highlights

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed
Our results demonstrate that local administration of IL-12 may overcome barriers encountered by Chimeric antigen receptor (CAR)-T cell therapy for GBM and provide a rationale for a combination treatment approach in clinical study
We showed in an orthotopic syngeneic model of glioma that a single intra-tumoral injection of IL-12:Fc combined with systemic infusion of CAR-T cells results in the eradication of advanced tumors, whereas either single treatment alone failed to control tumor growth

Summary

Introduction

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). Our findings show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM. CAR-T cell efficacy is impaired by an adaptive immune suppressive response, i.e. upregulation of immune inhibitory molecules, such as programmed cell death ligand-1 (PD-L1), indoleamine-2,3-deoxygenase 1 (IDO1), and infiltration of Tregs[10,11]. These results highlight the need for additional therapeutic strategies to counteract the hostile TME and overcome tumor heterogeneity. A delivery method which achieves the benefits of IL-12 in the TME without systemic toxicity is desirable[13,20]

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Conclusion