Oncolytic parvoviruses as cancer therapeutics

Rommelaere, Jean; Geletneky, Karsten; Angelova, Assia L.; Daeffler, Laurent; Dinsart, Christiane; Kiprianova, Irina; Schlehofer, Joerg R.; Raykov, Zahari

doi:10.1016/j.cytogfr.2010.02.011

Cited by 104 publications

(97 citation statements)

References 44 publications

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“…Rodent PVs are of particular interest in this regard because of their natural oncotropism, lack of preexisting antiviral immunity in most humans, and excellent safety profile (3). The suppressive activity of PVs against various rodent and human cancers has been documented in both in vitro systems and animal models (4,5).…”

Section: Oncolytic Pvsmentioning

confidence: 99%

“…PVs distinguish themselves by their dual oncolytic and immunostimulating activities, broad range of target tumors, ability to circumvent tumor cell resistance to conventional death inducers, and suitability for both local and systemic applications. Furthermore, their cytopathic effects can be recapitulated in vitro through the expression of a single parvoviral product, the nonstructural protein NS1, which functions as an oncogenic transformation-dependent toxin (3).…”

Section: Oncolytic Pvsmentioning

confidence: 99%

“…NS1 also interferes with cell survival at many levels. Direct interactions of NS1 with components of the DNA replication (RPA 1-3) and transcription (TBP, TFIIA, and SP1) machineries play a role both in viral DNA replication and transcription and in deregulating DNA/RNA metabolic processes in infected cells [3,4]. Other virus protein-cell protein interactions, such as NS1-CKII [5] and NS2-XPO1 [6], interfere with host cell signaling and nuclear export, respectively.…”

Section: Cell Disturbances and Pv Oncolysismentioning

confidence: 99%

See 2 more Smart Citations

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Nüesch

Lacroix

Marchini

et al. 2012

Clinical Cancer Research

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Rodent parvoviruses (PV) are recognized for their intrinsic oncotropism and oncolytic activity, which contribute to their natural oncosuppressive effects. Although PV uptake occurs in most host cells, some of the subsequent steps leading to expression and amplification of the viral genome and production of progeny particles are upregulated in malignantly transformed cells. By usurping cellular processes such as DNA replication, DNA damage response, and gene expression, and/or by interfering with cellular signaling cascades involved in cytoskeleton dynamics, vesicular integrity, cell survival, and death, PVs can induce cytostasis and cytotoxicity. Although productive PV infections normally culminate in cytolysis, virus spread to neighboring cells and secondary rounds of infection, even abortive infection or the sole expression of the PV nonstructural protein NS1, is sufficient to cause significant tumor cell death, either directly or indirectly (through activation of host immune responses). This review highlights the molecular pathways involved in tumor cell targeting by PVs and in PV-induced cell death. It concludes with a discussion of the relevance of these pathways to the application of PVs in cancer therapy, linking basic knowledge of PV-host cell interactions to preclinical assessment of PV oncosuppression. Clin Cancer Res; 18(13); 3516-23. Ó2012 AACR.

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Section: Oncolytic Pvsmentioning

confidence: 99%

Section: Oncolytic Pvsmentioning

confidence: 99%

Section: Cell Disturbances and Pv Oncolysismentioning

confidence: 99%

See 1 more Smart Citation

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Nüesch

Lacroix

Marchini

et al. 2012

Clinical Cancer Research

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“…In this regard, autonomous rodent parvoviruses (PVs), which have recently emerged as potential anticancer agents, deserve special attention. 3 This is because of their ability to replicate in and destroy cancer cells, while possessing low capacity for danger signalling and being innocuous to healthy tissues. 4 In particular, the oncolytic rat H-1PV was shown to selectively target and kill cells derived from various cancer types, including cells originating from human gliomas.…”

Section: Introductionmentioning

confidence: 99%

Activation of a glioma-specific immune response by oncolytic parvovirus Minute Virus of Mice infection

et al. 2012

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Rodent autonomous parvoviruses (PVs) are endowed with oncotropic properties and represent virotherapeutics with inherent oncolytic features. This work aimed to evaluate the capacity of Minute Virus of Mice (MVMp) to act as an adjuvant stimulating a mouse glioblastoma-specific immune response. MVMp was shown to induce cell death through apoptosis in glioma GL261 cells. Antigen-presenting cells (APCs) provide the initial cue for innate and adaptive immune responses, and thus MVMp-infected GL261 cells were tested for their ability to activate dendritic cells (DCs) and microglia (MG), two distinct cell types that are able to act as APCs. MG and discrete DC subsets were activated after co-culture with MVMp-infected glioma GL261 cells, as evidenced by upregulation of specific activation markers (CD80, CD86) and release of proinflammatory cytokines (tumor necrosis factor-a and interleukin-6). The in vivo analysis of immunodeficient and immunocompetent mice revealed a clear difference in their susceptibility to MVMp-mediated tumor suppression. Immunocompetent mice were fully protected from tumor outgrowth of GL261 cells infected ex vivo with MVMp. In contrast, immunodeficient animals were less competent for MVMp-dependent tumor inhibition, with only 20% of the recipients being protected, arguing for an additional immune component to allow full tumor suppression. In keeping with this conclusion, immunocompetent mice engrafted with MVMp-infected glioma cells developed a level of anti-tumor immunity with isolated splenocytes producing elevated levels of interferon-g. In rechallenge experiments using uninfected GL261 cells, we could show complete protection against the tumor, arguing for the induction of a T-cell-mediated, tumor-specific, long-term memory response. These findings indicate that the anticancer effect of PVs can be traced back not only for their direct oncolytic effect, but also to their ability to break tumor tolerance.

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“…Rodent cells are the natural hosts for H-1PV, but the virus will readily infect humans where it has been shown to be apathogenic. 1,2 One special characteristic of these rodent viruses is their absence of pathogenicity in adult animals and if any, is restricted to proliferating tissues and to fetuses or neonates. 3 H-1PV is considered oncotropic, efficiently infecting transformed human cell lines and human tumor cells, including melanoma, hepatoma, colon and gastric cancer cells [4][5][6] ; however, in contrast to these fast replicating cells, human immune cells and primary hepatocytes are not infected or lysed.…”

mentioning

confidence: 99%

Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

Sieben

Schäfer-Keller

Dinsart

et al. 2012

Intl Journal of Cancer

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This study aimed to investigate the function of toll-like receptors (TLRs) during oncolytic parvovirus H-1 (H-1PV)-induced human immune responses. First, the role of TLRs in the activation of the NFjB transcription factor was characterized; second, the immunologic effects of H-1PV-induced tumor cell lysates (TCL) on human antitumor immune responses were evaluated. A human ex vivo model was used to study immune responses with dendritic cells (DCs). Human embryonic kidney cells (HEK293) transfected to stably express TLRs were used as potential human DC equivalents to further investigate the role of specific TLRs during immune activation. TLR3 and TLR9 were activated by H-1PV infection, which correlated with NFjB translocation to the nucleus and a reduced cytoplasmic IjB expression. Using a TLR-signaling reporter plasmid (pNiFty-Luc), NFjB activity was increased following H-1PV infection. In addition, human DCs coincubated with H-1PV-induced TCL demonstrated increased TLR3 and TLR9 expression. These data suggest that H-1PV-induced TCL stimulate human DCs at least in part through TLR-dependent signaling pathways. Thus, DC maturation occurred through exposure to H-1PV-induced TCL through TLR-signaling leading to NFjB-dependent activation of the adaptive immune system as indicated by the increased expression of CD86, TLR3 and TLR9. Furthermore, the transcription of various cytokines indicates the activation of immune response, therefore the production of the proinflammatory cytokine TNF-a was determined. Here, H-1PV-induced TCL significantly enhanced the TNF-a level by DCs after coculture. H-1PV oncolytic virotherapy enhances immune priming by different effects on DCs and generates antitumor immunity. These findings potentially offer a new approach to tumor therapy.

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Oncolytic parvoviruses as cancer therapeutics

Cited by 104 publications

References 44 publications

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Molecular Pathways: Rodent Parvoviruses—Mechanisms of Oncolysis and Prospects for Clinical Cancer Treatment

Activation of a glioma-specific immune response by oncolytic parvovirus Minute Virus of Mice infection

Activation of the human immune system via toll‐like receptors by the oncolytic parvovirus H‐1

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