Altered expression of antiviral cytokine mRNAs associated with cyclophosphamide's enhancement of viral oncolysis

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 a/b, interferon g, TNFa, 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.

Triple Combination of Oncolytic Herpes Simplex Virus-1 Vectors Armed with Interleukin-12, Interleukin-18, or Soluble B7-1 Results in Enhanced Antitumor Efficacy

“…Published studies have shown that suppression of innate immunity can enhance the oncolytic virus replication and antitumor efficacy (48,49). Whether the expression of the immunostimulatory transgenes significantly affected the in vivo replication of vHsv vectors is yet to be determined.…”

Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model

“…These are all potential candidates for antivirus effects within gliomas. Many of these causes have been extensively described (Wakimoto et al, 2003(Wakimoto et al, , 2004, and some parameters have even been mathematically modeled (Wu et al, 2004). The low growth rate of the 4C8 glioma cells also poses a human-like barrier, given that human gliomas characteristically have a growth fraction that is much lower (2%-45%) than that seen with in vitro cultured human glioma cell lines.…”

Herpes simplex virus 1 (HSV-1) for cancer treatment

“…145 Efficient replication of the viral vector is critical to its antineoplastic activity. 49,50 The antitumor activity of hrR3 was enhanced by coadministration of cyclophosphamide (CPA). 49,50 It was speculated that CPA, a strong immunosuppressive agent, may temporarily suppress systemic anti-viral immunity, allowing increased replication of the therapeutic virus and thus an enhanced antitumor effect.…”

“…49,50 The antitumor activity of hrR3 was enhanced by coadministration of cyclophosphamide (CPA). 49,50 It was speculated that CPA, a strong immunosuppressive agent, may temporarily suppress systemic anti-viral immunity, allowing increased replication of the therapeutic virus and thus an enhanced antitumor effect. 50 Depletion of complement via cobra venom factor (CVF) treatment also facilitated in vivo viral propagation and improved antitumor activity of hrR3.…”

“…Both nonspecific (mediated by macrophages and natural killer cells) and specific immune responses (mediated by B and T cells) have been implicated as important host defenses against HSV-1 infections. [48][49][50][51][52][53] The relative value of each of these defense mechanisms varies significantly according to the genetic background of the host 54,55 and the route of viral inoculation.…”