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

Matthew McCord, Rimas V. Lukas, Christina Amidei, Nathan Demars, Arnold Gelb, Jill Buck, Sean Sachdev, Alexander Feldman, Matthew Tate, Karan Dixit, Daniel J. Brat, Lawrence Jennings, Craig Horbinski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Article numbervdab045
JournalNeuro-Oncology Advances
Issue number1
StatePublished - Jan 1 2021


  • DNA mismatch repair
  • IDH
  • glioma
  • immunotherapy

ASJC Scopus subject areas

  • Clinical Neurology
  • Oncology
  • Surgery


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