RRC ID 12740
Author Wakimoto H, Fulci G, Tyminski E, Chiocca EA.
Title Altered expression of antiviral cytokine mRNAs associated with cyclophosphamide's enhancement of viral oncolysis.
Journal Gene Ther.
Abstract Oncolytic viruses (OVs) are being used as anticancer agents in preclinical and clinical trials. Propagation of OVs inside infected tumors is critical to their efficacy and is mediated by the productive generation of progeny OVs within infected tumor cells. In turn, this progeny can spread the infection to other tumor cells in successive rounds of oncolysis. Previously, we had found that, in rats, cyclophosphamide (CPA) pretreatment increased infection of brain tumors by an intra-arterially administered herpes simplex virus type 1 OV, because it inhibited activation of complement responses, mediated by innate IgM. We also have previously shown that other pharmacologic inhibitors of complement, such as cobra venom factor (CVF), allowed for increased infection. However, in these studies, further inhibition of complement responses by CVF did not result in additional infection of brain tumor cells or in propagation of OV to surrounding tumor cells. In this study, we sought to determine if CPA did lead to increased infection/propagation from initially infected tumor cells. Unlike our results with CVF, we find that CPA administration does result in a time-dependent increase in infection of tumor cells, suggestive of increased propagation, in both syngeneic and athymic models of brain tumors. This increase was due to increased survival of OV within infected tumors and brain surrounding tumors. CPA's effect was not due to a direct enhancement of viral replication in tumor cells, rather was associated with its immunosuppressive effects. RT-PCR analysis revealed that CPA administration resulted in impaired mRNA production by peripheral blood mononuclear cells (PBMCs) of several cytokines (interferons alpha/beta, interferon gamma, TNFalpha, IL-15, and IL-18) with anti-HSV function. These findings suggest that the CPA-mediated facilitation of OV intraneoplastic propagation is associated with a general decrease of antiviral cytokines mRNAs in PBMCs. These findings not only suggest a potential benefit for the addition of transient immunosuppression in clinical applications of oncolytic HSV therapy, but also suggest that innate immunomodulatory pathways may be amenable to manipulation, in order to increase OV propagation and survival within infected tumors.
Volume 11(2)
Pages 214-23
Published 2004-1
DOI 10.1038/sj.gt.3302143
PII 3302143
PMID 14712306
PMC PMC2825886
MeSH Animals Brain Neoplasms / therapy Brain Neoplasms / virology Complement Inactivator Proteins / therapeutic use* Cyclophosphamide / therapeutic use* Cytokines / genetics Cytokines / metabolism* Gene Expression Glioma / therapy Glioma / virology Immunotherapy / methods* Models, Animal RNA, Messenger / metabolism* Rats Rats, Inbred F344 Rats, Nude Reverse Transcriptase Polymerase Chain Reaction Simplexvirus / physiology* Virus Replication / drug effects
IF 3.203
Times Cited 67
DNA material pRx-mIL4-bsr (RDB01887)