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    Keywords: EXPRESSION ; THERAPY ; MICE ; DENDRITIC CELLS ; T-CELLS ; MINUTE VIRUS ; vaccination ; autonomous parvovirus ; PANCREATIC-CANCER ; VIRUS-INFECTION
    Abstract: Treatment of cancers by means of viruses, that specifically replicate in (oncotropism) and kill ( oncolysis) neoplastic cells, is increasingly gaining acceptance in the clinic. Among these agents, parvoviruses have been shown to possess not only direct oncolytic but also immunomodulating properties, serving as an adjuvant to prime the immune system to react against infected tumors. Here, we aimed to establish whether immunomodulating mechanisms participate in the recently reported therapeutic potential of parvoviruses against pancreatic carcinoma. Using adoptive transfer experiments we discovered that the transfer of splenocytes of donor rats harboring H-1PV-treated orthotopic PDAC tumors could significantly prolong the survival of naive tumor-bearing recipients, compared to those receiving cells from mock-treated donors. Closer investigation of immunological parameters in infected donor rats revealed that virus-induced interferon gamma production and cellular immune response played an important role in this effect. These data have also preclinical relevance since abortive H-1PV infection of human peripheral blood mononuclear cells or cocultivation of these cells with H-1PV-preinfected pancreatic cancer cells, resulted in enhancement of innate and adaptive immune reactivity. Taken together our data reveal that oncolytic H-1PV modulates the immune system into an anticancer state, and further support the concept of using parvoviruses in the fight against pancreatic cancer.
    Type of Publication: Journal article published
    PubMed ID: 21124075
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  • 4
    Keywords: MINUTE VIRUS ; EPSTEIN-BARR-VIRUS ; TOLL-LIKE RECEPTORS ; NONSTRUCTURAL PROTEINS NS2 ; ADENOASSOCIATED VIRUS VECTORS ; NEWCASTLE-DISEASE-VIRUS ; PATHOGEN RECOGNITION ; INTERFERON-PRODUCING CELLS ; RIG-I ; I-LIKE RECEPTORS
    Abstract: The oncotropism of Minute Virus of Mice (MVMp) is partially related to the stimulation of an antiviral response mediated by type-I interferons (IFNs) in normal but not in transformed mouse cells. The present work was undertaken to assess whether the oncotropism displayed against human cells by MVMp and its rat homolog H-1PV also depends on antiviral mechanisms and to identify the pattern recognition receptor (PRR) involved. Despite their low proliferation rate which represents a drawback for parvovirus multiplication, we used human peripheral blood mononuclear cells (hPBMCs) as normal model specifically because all known PRRs are functional in this mixed cell population and moreover because some of its subsets are among the main IFN producers upon infections in mammals. Human transformed models consisted in lines and tumor cells more or less permissive to both parvoviruses. Our results show that irrespective of their permissiveness, transformed cells do not produce IFNs nor develop an antiviral response upon parvovirus infection. However, MVMp- or H-1PV-infected hPBMCs trigger such defense mechanisms despite an absence of parvovirus replication and protein expression, pointing to the viral genome as the activating element. Substantial reduction of an inhibitory oligodeoxynucleotide (iODN) of the latter IFN production identified TLR-9 as a potential PRR for parvoviruses in hPBMCs. However, neither the iODN treatment nor an antibody-induced neutralization of the IFN-triggered effects restored parvovirus multiplication in these cells as expected by their weak proliferation in culture. Finally, given that a TLR-9 activation could also not be observed in parvovirus-infected human lines reported to be endowed with a functional TLR-9 pathway (Namalwa, Raji, and HEK293-TLR9(+/+)), our data suggest that transformed human cells do not sense MVMp or H-1PV either because of an absence of PRR expression or an intrinsic, or virus-driven defect in the endosomal sensing of the parvovirus genomes by TLR-9.
    Type of Publication: Journal article published
    PubMed ID: 23383065
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; radiotherapy ; tumor ; TUMOR-CELLS ; AGENTS ; CELL ; Germany ; LUNG ; MODEL ; MODELS ; THERAPY ; SYSTEM ; TUMORS ; MICE ; TRANSDUCTION ; INFECTION ; REDUCTION ; RAT ; antibodies ; antibody ; TARGET ; virus ; VECTOR ; metastases ; US ; TRANSFORMATION ; VACCINE ; IMMUNE-RESPONSE ; vaccination ; TARGETS ; TUMOR CELLS ; CANCER-THERAPY ; EFFECTOR ; AGENT ; ONCOLOGY ; PROGRAM ; CAPACITY ; parvovirus ; oncolysis ; INTERLEUKIN-12 ; IMMUNE-SYSTEM ; TUMOR-CELL ; ANIMAL-MODEL ; TRANSFORMED-CELLS ; tumor targeting ; animal ; animal model ; IMPROVEMENT ; anticancer agent ; ANTICANCER AGENTS ; HOLD ; OSTEOSARCOMA LUNG METASTASES
    Abstract: Oncolytic viruses have emerged as a novel class of potent anticancer agents offering an improvement on chemo-and radiotherapy in terms of tumor targeting and reduction of side-effects. Among these agents, autonomous parvoviruses have attracted the attention of researchers for their ability to preferentially replicate in and kill transformed cells, and to suppress tumors in the absence of adverse reactions in various animal models. We have previously shown that lethally irradiated autologous tumor cells can support parvovirus H-1PV production and serve as carriers to deliver progeny H-1PV into the vicinity of lung metastases in a rat tumor model, resulting in H-1PV infection of and multiplication in metastatic cells. It is known that irradiated autologous (neoplastic) cells can also act as a therapeutic vaccine against the original tumor. Yet the ability of these cells to suppress metastases in the above model was found to be much increased as a result of their H-1PV infection. This prompted us to determine whether H-1PV boosted the tumor-suppressing capacity of the autologous vaccine by increasing its immunogenic potential and/or by making it a factory of oncolytic vi. ruses able to reach and destroy the metastases. Both effects could be dissociated in the presence of neutralising antibodies which either prevent the progeny viruses from spreading to metastatic cells, or deplete the CD8 effector cells from the immune system. This strategy revealed that the H-1PV infection of tumor cells enhanced their ability to trigger an immune response for which uninfected tumor cells could be the targets. thereby amplifying and taking over from the direct viral oncolytic activity. This dual oncolytic/vaccinal effect of H-1PV holds out promises of clinical applications to cancer therapy
    Type of Publication: Journal article published
    PubMed ID: 17487410
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  • 6
    Keywords: CELLS ; tumor ; Germany ; MICE ; NF-KAPPA-B ; ACTIVATION ; INFECTION ; MECHANISM ; mechanisms ; CYCLE ; IMMUNE-RESPONSES ; STIMULATION ; antibody ; MOUSE ; innate immunity ; INTERFERON ; FAILURE ; INFECTIONS ; DOUBLE-STRANDED-RNA ; S-PHASE ; VIRAL-INFECTION ; oncolytic virus ; LIFE ; PROTEIN-KINASE PKR ; TOLL-LIKE RECEPTOR-3 ; Intrinsic ; ALPHA/BETA INTERFERON ; KILHAM RAT VIRUS
    Abstract: Parvovirus minute virus of mice (MVMp) is endowed with oncotropic properties so far ascribed only to the dependency of the virus life cycle on cellular factors expressed during S phase and/or modulated by malignant transformation. For other viruses oncotropism relies on their inability to circumvent type I interferon (IFN)-induced innate antiviral mechanisms, the first line of defense triggered by normal cells against viral infections. These agents propagate, therefore, preferentially in transformed/tumor cells, which often lack functional antiviral mechanisms. The present study aimed at investigating whether antiviral processes also contribute to MVMp oncotropism. Our results demonstrate that in contrast to MVMp-permissive transformed mouse A9 fibroblasts, freshly isolated normal counterparts (mouse embryonic fibroblasts [MEFs]) mount, through production and release of type I IFNs upon their infection, an antiviral response against MVMp lytic multiplication. Pretreatment of MEFs with a type I IFN-beta-neutralizing antibody, prior to MVMp infection, inhibits the virus-triggered antiviral response and improves the fulfillment of the MVMp life cycle. Our results also show that part of the A9 permissiveness to MVMp relies on the inability to produce type I IFNs upon parvovirus infection, a feature related either to an A9 intrinsic deficiency of this process or to an MVMp-triggered inhibitory mechanism, since stimulation of these cells by exogenous IFN-beta strongly inhibits the parvovirus life cycle. Taken together, our results demonstrate for the first time that parvovirus infection triggers an innate antiviral response in normal cells and suggest that the MVMp oncotropism depends at least in part on the failure of infected transformed cells to mount such a response
    Type of Publication: Journal article published
    PubMed ID: 19864388
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  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; THERAPY ; MICE ; MECHANISM ; DENDRITIC CELLS ; T-CELLS ; MINUTE VIRUS ; vaccination ; INTERFERON ; pancreatic cancer ; autonomous parvovirus ; PANCREATIC-CANCER ; parvovirus ; VIRUS-INFECTION ; ADOPTIVE TRANSFER ; oncolytic ; immunomodulation ; Th1 response
    Abstract: Treatment of cancers by means of viruses, that specifically replicate in (oncotropism) and kill ( oncolysis) neoplastic cells, is increasingly gaining acceptance in the clinic. Among these agents, parvoviruses have been shown to possess not only direct oncolytic but also immunomodulating properties, serving as an adjuvant to prime the immune system to react against infected tumors. Here, we aimed to establish whether immunomodulating mechanisms participate in the recently reported therapeutic potential of parvoviruses against pancreatic carcinoma. Using adoptive transfer experiments we discovered that the transfer of splenocytes of donor rats harboring H-1PV-treated orthotopic PDAC tumors could significantly prolong the survival of naive tumor-bearing recipients, compared to those receiving cells from mock-treated donors. Closer investigation of immunological parameters in infected donor rats revealed that virus-induced interferon gamma production and cellular immune response played an important role in this effect. These data have also preclinical relevance since abortive H-1PV infection of human peripheral blood mononuclear cells or cocultivation of these cells with H-1PV-preinfected pancreatic cancer cells, resulted in enhancement of innate and adaptive immune reactivity. Taken together our data reveal that oncolytic H-1PV modulates the immune system into an anticancer state, and further support the concept of using parvoviruses in the fight against pancreatic cancer
    Type of Publication: Journal article published
    PubMed ID: 21124075
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  • 8
    Keywords: CANCER ; CANCER CELLS ; CELLS ; IN-VITRO ; AGENTS ; CELL ; Germany ; LUNG ; MODEL ; VITRO ; VIVO ; SYSTEM ; SYSTEMS ; TOOL ; GENOME ; ACTIVATION ; DNA ; IFN-GAMMA ; INFECTION ; MOTIFS ; MARKER ; RAT ; ANTIGEN ; ANTIGENS ; DENDRITIC CELLS ; LYMPH-NODES ; SIGNAL ; VARIANTS ; H-1 ; MATURATION ; virus ; VECTOR ; NUMBER ; metastases ; MARKERS ; HEPATOMA ; CANCER-CELLS ; Jun ; VACCINE ; REPLICATION ; IMMUNITY ; vaccination ; AGENT ; FEATURES ; ONCOLOGY ; NODES ; VARIANT ; CAPACITY ; GAMMA ; parvovirus ; EX-VIVO ; lung metastases ; IMMUNE-SYSTEM ; dendritic cell ; EVENTS ; signalling ; USA ; lymph nodes ; CANCER-TREATMENT ; SIGNALS ; TOOLS ; oncolytic ; GENOMES ; RAT MODEL ; H1PV ; CD86 ; OLIGODEOXYNUCLEOTIDE ; CpG motif ; ONCOLYTIC VIRUSES ; TLR-9 ; TOLL-LIKE-RECEPTOR-9
    Abstract: Oncolytic viruses represent novel tools for cancer treatment. Besides specifically killing cancer cells (oncolysis), these agents also provide danger signals, prompting the immune system to eliminate virus-infected tumours. As a consequence of oncolytic events, the innate and adaptive immune systems gain access to tumour antigens, which result in cross-priming and vaccination effects. Here the aim was to see whether we could enhance this adjuvant capacity by incorporating immunostimulatory CpG motifs into the single-stranded genome of an oncolytic parvovirus (H-1PV). We engineered 2 CpG-enriched H-1PV variants (JabCG1 and JabCG2), preserving both the replication competence and the oncolytic features of the parental virus. In keeping with their increased CpG content, the JabCG1 and JabCG2 genomes proved in vitro to be more potent triggers of TLR-9-mediated signalling than wild-type H-1PV DNA. Antitumour activity was evaluated in a rat model of MH3924A hepatoma lung metastases, where an infection with parental or modified viruses served as an ex vivo adjuvant to a subcutaneously administered autologous cell vaccine. In this setup, which excludes direct oncolytic effects on metastases, the JabCG2 vector displayed enhanced immunogenicity, inducing markers of cellular immunity (IFN gamma) and dendritic cell activation (CD80, CD86) in mediastinal (tumour-draining) lymph nodes. This led to a significantly reduced metastatic rate (50%) as compared to other vaccination schedules (H-1PV-, JabCG1-, JabGC- or mock-treated cells). The data provide proof of principle that increasing the number of immunostimulatory CpG motifs within oncolytic viruses makes it possible to improve their overall anticancer effect by inducing antitumour vaccination. (C) 2008 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 18360875
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