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

doi:10.1073/pnas.0605496103

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 journal › Article › peer-review

312 Scopus citations

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 language	English (US)
Pages (from-to)	12873-12878
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	34
DOIs	https://doi.org/10.1073/pnas.0605496103
State	Published - Aug 22 2006
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Brain tumor
Gene therapy
Herpes simplex virus
Innate immunity
Oncolytic virus

ASJC Scopus subject areas

General

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10.1073/pnas.0605496103

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

Fulci, G, Breymann, L, Gianni, D, Kurozomi, K, Rhee, SS, Yu, J, Kaur, B, Louis, DN, Weissleder, R, Caligiuri, MA & Chiocca, EA 2006, 'Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 34, pp. 12873-12878. https://doi.org/10.1073/pnas.0605496103

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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.",

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AU - Yu, Jianhua

AU - Kaur, Balveen

AU - Louis, David N.

AU - Weissleder, Ralph

AU - Caligiuri, Michael A.

AU - Chiocca, E. Antonio

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AB - 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.

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KW - Gene therapy

KW - Herpes simplex virus

KW - Innate immunity

KW - Oncolytic virus

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Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses

Abstract

UN SDGs

Keywords

ASJC Scopus subject areas

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