Disappearance of MMR-deficient subclones after controlled IL-12 and PD-1 inhibition in a glioma patient

Abstract

Recurrent high-grade gliomas are aggressive brain tumors with a poor prognosis. They remain an unmet medical need, in part because of an incomplete understanding of the immunosuppressive tumor microenvironment. Although immune checkpoint inhibitors targeting programmed death 1 (PD-1) may have a therapeutic role, their efficacy may be limited by a paucity of tumor-infiltrating lymphocytes. Recently, the Controlled IL-12 gene therapy system has shown promise in increasing glioma immunogenicity. This system stimulates local IL-12 production through a locally administered adenoviral vector, which delivers genetic information for IL-12 and a transcription switch. An orally administered activator ligand, veledimex (VDX), controls transcription levels. IL-12 activity leads to downstream production of IFN-γ and increases tumor immunogenicity.1 A recent phase 1 clinical trial showed that Controlled IL-12 therapy was associated with increased expression of PD-1 and PD-L1 in tumor-associated T-cell infiltrates in glioma.1 This supports the concept of investigating Controlled IL-12 in combination with immune checkpoint inhibitor therapy. Here, we describe the case of a patient with a recurrent grade 4 astrocytoma in which post-temozolomide (TMZ) DNA mismatch repair (MMR)-deficient tumor subclones disappeared following administration of Controlled IL-12 with PD-1 blockade. These data demonstrate that the immune system can be engaged to target high-grade glioma.