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

293 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

Keywords

Brain tumor
Gene therapy
Herpes simplex virus
Innate immunity
Oncolytic virus

ASJC Scopus subject areas

General

UN SDGs

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

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10.1073/pnas.0605496103

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

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AU - Fulci, Giulia

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AU - Gianni, Davide

AU - Kurozomi, Kazuhiko

AU - Rhee, Sarah S.

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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N2 - 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.

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

Keywords

ASJC Scopus subject areas

UN SDGs

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