Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses

Giulia Fulci, Laura Breymann, Davide Gianni, Kazuhiko Kurozomi, Sarah S. Rhee, Jianhua Yu, Balveen Kaur, David N. Louis, Ralph Weissleder, Michael A. Caligiuri, E. Antonio Chiocca

Research output: Contribution to journalArticle

241 Citations (Scopus)

Abstract

Clinical trials are testing oncolytic viruses (OVs) as therapies for cancer. We have shown that animals that have brain tumors and are treated with a herpes simplex virus (HSV)-derived OV live significantly longer when cyclophosphamide (CPA) is preadministered. Here, we explore the mechanisms behind this finding. In a syngeneic rat glioma model, intratumoral HSV administration is associated with rapid increase of natural killer cells, microglia/macrophages (CD68+ and CD163+), and IFN-γ. Pretreatment with CPA enhances HSV replication and oncolysis and reduces an HSV-mediated increase in CD68+ and CD163+ cells and intratumoral IFN-γ. Molecular imaging shows CPA pretreatment to inhibit HSV-induced infiltration of tumor-associated phagocytic cells. Our results reveal molecular and cellular mechanisms that inhibit intratumoral spread of HSV and suggest a therapeutic path for improving the efficacy of virotherapy as a treatment for cancer.

Original languageEnglish
Pages (from-to)12873-12878
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number34
DOIs
Publication statusPublished - Aug 22 2006
Externally publishedYes

Keywords

  • Brain tumor
  • Gene therapy
  • Herpes simplex virus
  • Innate immunity
  • Oncolytic virus

ASJC Scopus subject areas

  • General

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  • Cite this

    Fulci, G., Breymann, L., Gianni, D., Kurozomi, K., Rhee, S. S., Yu, J., Kaur, B., Louis, D. N., Weissleder, R., Caligiuri, M. A., & Chiocca, E. A. (2006). Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses. Proceedings of the National Academy of Sciences of the United States of America, 103(34), 12873-12878. https://doi.org/10.1073/pnas.0605496103