Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses.
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Journal: 2006/September - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
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-gamma. Pretreatment with CPA enhances HSV replication and oncolysis and reduces an HSV-mediated increase in CD68+ and CD163+ cells and intratumoral IFN-gamma. 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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Proc Natl Acad Sci U S A 103(34): 12873-12878
PMID: 16908838

Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses

+2 authors
*Dardinger Center for Neuro-Oncology and Neurosciences, Department of Neurological Surgery, James Cancer Hospital and Solove Research Institute, Ohio State University Medical Center, Columbus, OH 43210;
Molecular Neuro-Oncology Laboratories, Neurosurgery Service,
Center for Molecular Imaging Research, and
Pathology Service, Massachusetts General Hospital, East Building, 13th Street, Charlestown, MA 02129; and
Ohio State University Comprehensive Cancer Center, Columbus, OH 43210
To whom correspondence should be addressed at: Dardinger Center for Neuro-Oncology and Neurosciences, Department of Neurological Surgery, Ohio State University Medical Center, N-1017 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210., E-mail: ude.cmuso@accoihc.ae
Communicated by Avner Friedman, Ohio State University, Columbus, OH, July 4, 2006.

Author contributions: G.F. and E.A.C. designed research; G.F., L.B., D.G., K.K., S.S.R., J.Y., and B.K. performed research; D.N.L., R.W., and M.A.C. contributed new reagents/analytic tools; G.F. analyzed data; and G.F. and E.A.C. wrote the paper.

Received 2006 Mar 3
Copyright © 2006 by The National Academy of Sciences of the USA

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.

Keywords: gene therapy, innate immunity, oncolytic virus, brain tumor, herpes simplex virus
Abstract

Advances in virology and tumor biology have enabled development of oncolytic viruses (OVs), which replicate selectively in tumor cells (1–6). OV progeny propagate throughout tumors, lysing tumor cells but not normal cells. Phase I clinical trials have shown OV therapy to be safe (7–13) but with limited efficacy. A brisk host response to OV therapy has been seen. It includes intratumoral immune cells (7) and acute-phase reaction to intravascular virus (13). Innate immune responses may be a common side effect of OV therapy, similar to the radionecrosis of radiotherapy or myelosuppression of chemotherapy.

The role of host immune responses in the efficacy or toxicity of OV therapy is poorly defined. Such responses are thought beneficial because oncolysis stimulates adaptive immunity, setting up an anticancer vaccination effect (14–16). However, initial innate responses to OVs may reduce efficient anticancer effects (17–21). For example, we have shown a herpes simplex virus (HSV)-based OV therapy to be more efficient when cyclophosphamide (CPA) is present (22–25), and this increased efficiency is credited to CPA's immunosuppressive action. However, the specific immune pathways of the observed effects have not been analyzed.

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Acknowledgments

This work was supported by National Institutes of Health Grants P01 CA69246, NS41571, and R01 CA85139 (to E.A.C.) and CA95426, CA16058, and CA68458 (to M.A.C.).

Acknowledgments

Abbreviations

CPAcyclophosphamide
4HC4-hydroxy-CPA
MIONmonocrystalline iron oxide particle
OVoncolytic virus
NKnatural killer
HSVherpes simplex virus
IHCimmunohistochemistry.
Abbreviations

Footnotes

Conflict of interest statement: No conflicts declared.

Footnotes

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