At the 4th meeting of the European Seminars of Virology (EuSeV), organized by the European Society of Virology (ESV) at the University of Bologna Residential Centre in Bertinoro, Italy, scientists from all over Europe, the US and Canada presented data and reviewed up-to-date knowledge on the complex and multifaceted relationship between viruses and cancer. The titles of the two parts of the meeting (Mechanisms of Viral Oncogenesis and Viral Oncolysis and Immunotherapy) hinted at how viruses can be, so to say, the “main causing agents” or the “worst enemies” of cancer depending on the context. Oncogenic viruses promote dysregulated cell growth, leading to malignant transformation in a fraction of infected patients, and are estimated to cause approximately up to 15%-20% of all human cancer cases. Even though high risk HPV genotypes, such as HPV16 and HPV18, are perhaps the principal oncogenic viruses, Epstein Barr Virus (EBV), KSHV, HBV, HCV and the recently discovered human polyomaviruses such as Merkel cell carcinoma virus, are also frequently associated with neoplasms. Studying oncogenic viruses has been of fundamental importance in the recent past from a basic science point of view, in order to understand molecular carcinogenesis mechanisms, but it is still a very rewarding field of investigation for dissecting key biological issues related to cell growth and differentiation. Furthermore, viral oncology discloses exciting therapeutic perspectives for virus-associated cancers, either by pharmacologically targeting viral oncogenic proteins (for example the PDZ binding domain of the HPV E6 protein, or the EBV LMP protein), or by eliciting an immune response against the same proteins. Thus, therapeutic vaccination with a synthetic long peptide encompassing the E6 and E7 HPV proteins yielded very good results in patients with HPV-associated intraepithelial neoplasia.
On the other hand, it has been known for quite a long time that cancer cells seem to be more susceptible to viral infection: even viruses which can’t establish a productive infection in normal human cells are able to infect and kill cancer cells. Malignant cells are often defective in innate antiviral response pathways that imply stopping protein synthesis, presenting antigens to the immune system, or triggering cell death by apoptosis. Though some attempts to use cancer-killing viruses (oncolytic viruses – OVs) had already been made at the beginning of the 20th century, it was only at the end of the same century that the implementation of molecular biology and genetic enigneering techniques enabled scientists to rationally design mutant viruses with enhanced safety and selectivity for cancer. Genetically engineered oncolytic viruses usually have deletions of genes essential for virulence in healthy but not in cancer cells, but they can also be “armed” with the insertion of foreign genes with a therapeutic effect.
A major breakthrough in the oncolytic viruses field was the approval by the FDA in 2015 of talimogene laherparepvec, an engineered HSV-1 which is unable to infect neurons and expresses the immunostimulatory protein GM-CSF, for patients with unresectable stage IIB-IV melanoma. Nowadays, oncolytic viruses are one of the most promising novel therapeutic tools against cancer.
A very diverse array of viruses has been tested, including viruses which usually infect non-human animals, such as Newcastle Disease virus, members of the Rhabdoviridae and Parvoviridae families, as well as attenuated human pathogens, e.g adenoviruses and herpes simplex virus. It also became clear that the most important mechanism of action of oncolytic viruses is immuno-mediated, as they can induce immunogenic cell death and subvert the immunosuppressive tumor microenvironment to trigger an anti-cancer immune response. In this way, oncolytic viruses are a powerful tool for cancer immunotherapy: also, many of the therapeutic genes with which engineered OVs are “armed” encode for cytokines or other immunologically active proteins.
The scientific reports of the 4th EuSeV have been summarized by the presenting authors in the following section of this edition of the ESV newsletter.
President of the European Society for Virology
Oncolytic Viruses: Quo Vadis?
Carmela Passaro and E. Antonio Chioccia, Brigham and Women’s Hospital, Boston, MA, USA
In June 2016 the so called “Balcony of Romagna”, Bertinoro, hosted the 4th European Seminar in Virology (EuSeV). Surrounded by a Medieval castle, a panel of experts in oncogenic and oncolytic viruses met to discuss about the recent advances achieved in this field.
Oncolytic viruses (OVs) are now considered a new class of immunotherapy. Applied as a single agent they combine the ability to directly kill tumor cells and stimulate immune responses against cancer, obtaining a therapeutic effect both at local and at distant sites.
The interest in oncolytic virotherapy has been renewed after the approval by the FDA of the first oncolytic virus for the treatment of advanced melanoma. Indeed, Imlygic (Talimogene Laherparepvec or T-VEC), an oncolytic herpes virus that encodes for the immunostimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF), demonstrated an improved durable response rate in a randomized Phase III clinical trial.
Many viruses are currently exploited as vectors for oncolytic virotherapy. Several groups are working in addressing which is the best virus in the context of each tumor. To date the effectiveness of Adenovirus, Herpes-Simplex virus, Vaccinia Virus, Reovirus, Seneca Valley Virus, and Coxsackievirus as anti-cancer agents have been shown in a broad range of preclinical cancer models. During the 4th European Seminar in Virology (EuSeV), new promising oncolytic viruses were also discussed. Dr Bell showed results for Maraba virus as a platform to engineer a new oncolytic Rhabdovirus. Dr Geletneky proved the safety of the oncolytic parvovirus H-1 in a clinical trial enrolling patients with recurrent glioblastoma. Furthermore, Ammour and colleagues suggested that attenuated vaccine strains L-16 of measles virus and L-3 of mumps virus could be potential oncolytic agents against pediatric acute leukemia.
The outcome of virotherapy is highly dependent on the type of tumor cells, on the viral vector used and its interaction with tumor cells, and on the interplay between the virus, tumor microenvironment and host immune system. Normal cells evolved several mechanisms to respond to viral infection. Most of cancer cells lost these mechanisms and therefore they result permissive for viral replication of attenuated virus used as oncolytics. However some tumor type can still counteract viral infection influencing in this way the therapeutic effect of OVs. In this regards, Delaunay and colleagues in their presentation showed that the sensitivity of malignant pleural Mesothelioma to measles virus infection directly depends on defects of Type I Interferon response.
Moreover, Dr Campadelli-Fiume showed new retargeting strategies for oncolytic HSV that allow for the use of less attenuated and highly cancer-specific oncolytic viruses. These viruses are able to replicate and spread despite intrinsic defects and heterogeneity in the cancer cell population.
Although the immune response is an essential feature of the OV-induced anti-tumor effect, it can also represent a double-edge sword for viral cytotoxicity by limiting viral replication and spreading. Dr. Chiocca discussed results for a specific glioma-stem cell targeted oncolytic HSV and also showed that HDAC inhibition can improve viral replication by altering trafficking of post-entry virions to nuclei for replictaion rather than lysosome for xenophagy.
Another promising anti-cancer approach is to combine oncolytic viruses with checkpoint inhibitors. Indeed it has been demonstrated that OVs can kill cancer cells by inducing the immunogenic cell death followed by the release of tumor-associated antigen (TAA) that can stimulate the immune system against tumor cells. Moreover, OVs induce interferon release in the tumor microenvironment that can upregulate PD-L1 expression, sensitizing tumors to checkpoint inhibitors treatment. Several strategies are under evaluation to further potentiate this combinatorial therapy. The future development of this new class of drugs will lead to development of OVs armed with immunomodulatory molecules or with TAA to use in conjunction with checkpoint inhibitors to finally re-direct/re-activate the immune response against cancer.
4th European Seminar in Virology (EuSeV), Oncogenic and Oncolytic Viruses, 10/06/2016-12/06/2016, Bertinoro: Overview of the Discussed Topics
Compiled by Attendees from Campadelli-Fiume Laboratory, Department of Experimentall, Diagnostic and Specialty Medicine, University of Bologna, Italy: E. Avitabile, C. Casiraghi, E. Gabev, V. Gatta, T. Gianni, V. Leoni, R. Massaro, L. Menotti, B. Petrovich, A. Vannini
The 4th European Seminar in Virology (EuSeV) covered two aspects of the interplay between viruses and tumors: viral oncogenesis and virus-based anticancer therapeutics.
With regards to the mechanisms of viral oncogenesis, lectures were given about human papilloma-, hepatitis, herpes-, lenti- and retro- viruses.
Banks L. (International Centre for Genetic Engineering and Biotechnology, Trieste, Italy): Mechanisms underlying Human Papillomavirus Induced Malignancy
Human Papillomaviruses (HPVs) are responsible for about 5% of all human cancers, in particular they induce approximately 100% of cervical cancers. Over 200 different types of HPV have been described, but only a small subset of 12 so-called high-risk types are cercinogenic, in particular HPV16 and HPV18. The cooperative action of two viral oncoproteins, E6 and E7, is necessary for tumor initiation and progression, but also for tumor maintenance. Since inhibition of either E6 and E7 expression results in cell growth arrest and apoptosis, these proteins represent excellent targets for therapy against HPV-induced malignancy. In thes work Banks demonstrated that the regulation of E6 activity is linked to the control of cellular signaling pathways. A critical role is played by a highly conserved PDZ binding motif (PBM), and contributes to thte development of malignancy.
Bartenschlager R. (University Medical Center, Heidelberg, Germany): New Insights into the Biology of Oncogenic Hepatitis Viruses
Chronic hepatitis C and B are the main risk factors for the development of hepatocellular carcinoma (HCC). R. Bartenschlager illustrated some new insight into the biology of this two oncogenic viruses. In the first part of his talk he focused on the host miRNA 122, involved in the regulation of fatty acid metabolism and usd by HCV for productive replication. HCV can sequester miR-122 in vitro and derepresses endogenous miR-122 targets. The second part of his talk focused on the L-protein of the envelope of HBV. He illustrated how L-protein is capable to adopt two alternate topologies with domain either located at the inside or the outside of the viral membrane. In this way the regions involved in the binding of HBV to its receptors (HSPG and NTCP) are exposed ony when the virus reaches its final destination.
Kieser A. (Helmholtz Centre, Munich, Germany): The LMP1 Oncoprotein of Epstein-Barr Virus: Highjacker of B-Cell Signaling
The EBV infection of B-cells contributes to cell transformation by mimicking host cell factors involved in B-cell survival and activation. The major oncoprotein LMP1 mimics CD40 signals through the recruitment of signaling proteins (e.g. TRAF), which in turn induce NF-kB, MAPK and PI3K signaling in the infected cells. Effects of LMP1 activities are: cell proliferation, block of apoptotic pathways.
Giordano A. (Temple University, Sbarro Health Organization, Philadelphia, USA, and University of Siena, Italy): Rb Family: Link between Viruses and Cancer
A. Giordano discussed the role of pRB family proteins in cell cycle progression, highlighting the molecular mechanisms by which many viral proteins induce viral transformation by pRB inactivation. He presented recent results with a new adeno-oncolytic virus, which lacks pRB binding proteins and can selectively replicate only in tumor cells with modified pRB pathways.
Caruso A. (University of Brescia, Italy): Role of HIV Matrix Protein p17 Variants in Lymphoma Pathogenesis
Lymphomas represent the most common type of cancer in HIV+ patients, although the HIV-1 genome is not detectable in malignant B cells. A. Caruso investigated the role of the HIV-1 matrix protein 17, since it accumulates and persists in lymph nodes even during cART, triggers and sustains aerrant B lymphocyte activation, promotes angiogenesis and lymphangiogenesis. Moreover, patients with NHL, but not patients without lymphoma, carry the clonogenic p17 variants; this variants display a potent B-cell growth-promoting activity, which is exerted by activating the Akt signaling pathway.
Thoma-Kress A. (Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany): Molecular Mechanisms of HTLV-1 Transmission
HTLV-1 is the only human retrovirus known to cause neoplasia, adult T-cell leukemia/lymphoma. Infection and tramsmission occurs via cell-cell contact, either by viral budding into synaptic clefts, or tranfser of viral biofilms at virological synapses. Tax-1 and p8 are the viral proteins that have been identified as key players in the above mechanisms, for the formation of the virological synapse and for cellular conduits induction, repsectively. Both act extensively on the host cell cytosekeleton and remodel it to achieve the formation of the virus-transmission structures. Notably, Fascin, an actin-bundling cellular protein, is overexpressd in HTLV-1 infected cells.
Neipel F. (Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany): Mechanisms of Oncogenesis by Kaposi-Sarcoma Associated Herpesvirus
KHSV causes three human malignacies (KS, PEL, MDC) and is an extraordinary example of viral piracy of many cellular genes. It exploits its viral homologs of cellular genes involved in cell cycle, apoptosis and interferon response regulation, to highjack the cellular pathways. Studies are hindered by the lack of an in vitro system of de-novo transformation in cell culture. The ability of PEL cells to grow in cell culture allowed the identification of viral genes involved in their transformation. The more recent evidence in this field is the pleiotropic role of vIRS (1, 2 and 3) in interferon antagonism and cell cycle regulation.
The Viral Oncolysis and Immunotherapy sessions covered strategies exploiting herpes-, vaccinia-, adeno- viruses against different types of cancers.
Becker J. (University Duisburg Essen/DKFZ, Translational Skin Cancer Research/dermatology, Essen/Heidelberg, Germany): Immunotherapy of Advanced Skin Cancer: From Biomarker to Means to Overcome Escape Mechanisms
Becker presented an overview of the state of the art of the treatment of advanced melanoma. Antibodies targeting immune checkpoint molecules like PD-1 and CTLA-4 are improving the immune response against cancer cells in patients with disseminated melanoma. Combination therapies composed of anti-PD-1 and the recently approved oncolytic virus T-VEC are now tested in clinical trials. These two molecules could act in synergy to elicit a potent anti-cancer reponse mediated by both cytotoxic CD8 T cells and NK cells.
Chiocca E.A. (Brigham and Women’s Hospital, Dana Farber Cancer Center, Boston, USA): Multiple Anti Cancer Mechanisms of Oncolytic HSVs
Chiocca reviewed multiple anticancer mechanisms of oncolytic virus-based immunotherapies, and focused on the promising results obtained with tumor-selective o-HSVs and viral-based vectors. He discussed recent data on combinatorial usage of oHSV, including o-HSVs armed with immunomodulating moecules, o-HSVs combined with pharmacological or chemical adjuvants, which synergize with virotherapy in humans. He also shared his experience in the approach with FDA for approval of o-HSV for clinical trials.
Wang Y. (Queen Mary University of London, Barts Cancer Institute, London, United Kingdom): Promises of the Lister Strain of Vaccinia Virus as an Anti Cancer Immunotherapeutic Agent
- Wang has pioneered the clinical application of the Lister strain of vaccinia virus as an oncolytic agent. This virus appears to be superior to other oncolytic agents in its ability to be administered systemically. Wang critically discussed the pitfalls of vaccinia strains that, unless they are higly attenuated, may cause local vaccinia-induced lesions. Finally, he covered the issue of novel tumor targeted Vaccinia viruses as immunotherapeutic agents.
Nettelbeck D. (German Cancer Research Center (DKFZ), Heidelberg, Germany): Virus Engineering-Opportunities for Next Generation Virotherapeutics
The lecture of Nettelbeck covered different engineering strategies to improve oncolytic agents. In the first part of his talk he illustrated the approach for the retargeting of adenovirus through the insertion in the short HAdV-41 fiber knob domain of a ligand to EphA2 (receptor tyrosine kinase), overexpressed in various tumors, and functionally associated with tumor progression. Then, he focused on genetic delivery of a small immunoRNase consisting of an EGFR-binding ScFv antibody fragment fused to the RNase Onconase (ONC(EGFR)) that induces tumor cell death by RNA degradation after cellular internalization. Finally he compared the constitutive and inducible (delayed) expression of IL-2 by an oncolytic vaccinia virus and showed that regulation of IL-2 expression resulted in an enhanced safety and improved tumor-specific viral replication.
Campadelli-Fiume G. (University of Bologna, Bologna, Italy): Retargeting Strategies of Oncolytic HSVs
Campadelli-Fiume reviewed the strategy pursued by her laboratory. Essentially, the oncolytic HSV approved as therapeutic and those which are being tested in clinical trials are attenuated viuses, which gain their cancer specificity from defects in the cancer cell to mount a strong innate response to the virus. The tropism retargeting strategy leaves the virus virulence un-altered. The retargeted oncolytic HSVs gain their cancer specificity from changes in viral tropism, such that the viurs only infect cancer cells, and fail to infect the usual targets. The tropism retargeting has been achieved by insertion of single chain antibodies in the glycoproteins essential for HSV entry – gD, gH, or gB. These retargeted viruses exerted therapeutic effects in pleclinical studies. Thier effect in immunocompetent mouse models is being evaluated.
Jia W. (University of British Columbia, Vancouver, Canada): Oncolytic HSV-1 with Enhancement of Both Oncolyis And Safety
W. Jia illustrated different types of engineered oncolytic herpesviruses (o-HSVs), capable to replicate only in cancer cells, to improve safety without affecting oncolysis. The strategy consists in the transcriptional and/or translational regulation of essential viral genes, like ICP4 and ICP27. For example, transcriptional regulation can be achieved through miRNAs that are abundantly expressed in cancer but not in normal cells. A region complementary to the antisense of a cancer specific miRNA is integrated in the 3′-UTR of the ICP4 mRNA. If the miRNA is expressed, ICP4 mRNA is degraded. Different types of dual or triple regulated o-HSVs are being developed and successfully tested for safety and efficacy in pre-clinical models.
The most recent approaches to exploit oncolytic viruses as immunotherapeutic agents, i.e. anticancer vaccines, were also presented:
van der Burg S. H. (Leiden University Medical Center, Leiden, The Netherlands): Therapeutic Vaccination for Treatment of Human Papilloma Virus Induced Disease
Some HPV show oncogenic potential and cause cancer in oropharynx, cervix, vulva, vagina, penis and anus. In keratinocytes, HPV blocks the immune response up to two years interfering with the innate and adaptive immune system. The immune system can play a role in HPV cancer protection. For instance: CD8 T infiltrating cells are associated with lack of lymph node metastases in voluminous tumor, IFNgamma producing T cells are associated with increase in disease free survival. M1 macrophages are independent positive prognostic factors for survival. Regression of tumor is associated with HPV specific T cell reactivity. However, the role of adaptive immunity appears to be weak. In order to restore immune response to HPV, van der Burg’s group developed a synthetic long peptide vaccine made of overlapping E6/E7 peptides (SLP). Vaccination resulted in complete regression of tumor in mouse models. The vaccine is clinically active and associated with strong and broad T cell immunity. However, it exerted a weaker effect in advanced gynecological cancers. Abnormal levels of myeloid cells were detected in patients and mice with HPV-induced cancer. The treatment with the combination with carboplatin and paclitaxel was evaluated, in order to decrease myeloid cells. Adequately timed HPV16 SLP vaccination during carboplatin paclitaxel administration resulted in strong proliferative HPV16-specific T cell immunity.
Geletneky K. (Klinikum Darmstadt, Darmstadt, Germany): Oncolytic Parvoviruses
The parvovirus H-1 (ParvOryx01) trial was the first clinical trial with oncolytic viurses conducted in Europe on recurrent GBM patients, therefore it was put under special scrutiny and controls, leading to even stricter treatment and hospitalization schedules as compared to similar trials authorized in the US. Patients treated with different doses 10^9 to10^10 PFU and administration routes (intra- + peri- tumoral or intra-venous) showed overalls safety of the treatment and importantly the ability of the oncolytic virus to cross the blood-brain barrier and elicit virus-induced immune-mediated antitumor effects.
Kühnel F. (Medical School Hannover University, Hannover, Germany): Oncolytic Viruses as Anticancer Vaccines, Modifications of Cell Migration, Cell-Cell Contact And Angiogenesis
The oncolytic viruses fulfill their anti-tumor effects not only through the direct lysis of cancer cells, but also inducing the release of immunogenic molecules and eliciting an inflammatory stimulus, which interfere with the immunotolerant microenvironment of cancer. Hence, the oncolytic viruses can be used as perfectly shaped anticancer vaccine in situ, which covers the full antigenic spectrum of a tumor. Co-administration of oncolytic viruses with treatments that amplify the T-cell responses results in a more potent anti-tumor effect.
Bell J. (The Ottawa Hospital Research Institute, Ottawa, Canada): Development of an Oncolytic Rhabdovirus Platform
Bell’s talk covered the notion that oncolytic viruses may be employed in cancer therapy to deliver an “in situ” vaccine against the tumor. To achieve this goal, his group has been working on a “prime and boost” protocol, which combines a non replicating adenovirus (carrying a tumor antigen) as the priming agent, with a replication competent oncolytic virus (engineered to express the same antigen and able to replicate in tumor cells) as the boosting agent. For the boost phase, most interesting results were obtained with the Maraba virus, a rhabdovirus recently characterized as a potent oncolytic virus. The i.v. delivery of Maraba virus results in modifications of the tumor microenvironment. The oncolysis creates an in situ vaccine, capable to elicit a T-cell response against the tumor. Bell emphasized the benefits of rapidly translating laboratory data to the clinics, and receiving feed-backs from the clinics to the lab. This approach has been proved.
Selected communications from submitted abstracts covered the following:
Schneider J. et al. (NMI TT Pharmaservices, Berlin, University of Tübingen, Tübingen, Germany, Hannover Medical School, Hannover, Germany, Friedrich-Loeffler-Institute, Insel Riems, Germany): Evaluation of Bank Vole Hepacivirus (BvHV) as Model for Hepatitis C Using DigiWest Multiplex Protein Profiling
Hepatitis C virus (HCV) is associated with the development of liver cirrhosis and hepatocellular carcinoma. However, no suitable animal models to study the pathogenesis of HCV exist so far. One possible alternative might be experimental infection of bank voles with vole hepacivirus (vHV), which higly resembles HCV pathogenesis in humans. Using DigiWest protein profiling, a high-throughput technology, the authors aim to analyze liver samples of BvHv infected vs non-infected voles for 90 host proteins involved in several signaling pathways.
Cassaniti I. et al. (Fondazione IRCCS Policlinico San Matteo, Universities of Padova and Pavia, Italy): A New Tool for the Evaluation of HPV16-Specific T-Cell Response in Healthy Subjects
High-risk Human Papilloma Viruses (HPVs), namely types 16, 18, 31, 33 and 35, are associated to approximately 5% of cancer worldwide. Cassaniti evaluated HPV 16-memory T-cell response through ELISPOT and neutralization assays in 33 young healthy subjects, seven of which were vaccinated. 25 of 33 subjects were negative for specific neutralizing antibodies; they demonstrated that the antigen specific T-cell response was significantly higher in seropositive subjects while there was no correlation between the two assays.
Messa L. et al. (University of Padova, Padova, Italy, International Centre for GEnetic Engineering and Biotechnology, Trieste, Italy, University of Perugia, Perugia, Italy): Blocking a Highly-Conserved, Dual Binding Site of HPV E6 Oncogenic Protein to Develop New Anticancer Drugs
High-risk human papillomaviruses (HR-HPV) are the most common cause of cervical cancer and different types of head and neck cancers. During persistent HR-HPV infection, the expression levels of two oncoproteins, E6 and E7, drastically increase and the activity of E6 is responsible for malignant cell transformation. E6 induces the proteasome-mediated degradation of many cellular proteins important for cell cycle control and differentiation, such as p53. Recent studies revealed the importance of a conserved alpha-helix (alpha2) for the degradation of p53, but is also important for E6 self-association. In his work, Messa performed an in silico drug screening and identified some compounds fitting on a druggable cavity on a alpha2-helix. Then, through an ELISA-based E6 homodimerization assay and other in vitro assays, he identified two compounds able to disrupt E6 self-association and E6-mediated p53 degradation, and able to affect the viability of tumoral HPV-positive cells.
Karam L. et al. (Lebanese University, American University of Beirut, Beirut, Lebanon, Biogem Research Institute, Ariano Irpino, Italy, University Hospital Erlangen, Erlangen, Germany): The Anti-Tumor Activities of the Synthetic Retinoid ST1926 Against HHV8-Associated Primary Effusion Lymphoma
Primary effusion lymphoma (PEL) is a neoplasm caused by HHV8 infection, which transforms the infected B lymphocytes into malignant cells through the expression of viral oncogenes. The novel synthetic retinoid ST1926 has a potent anti-tumor activity against many malignancies, including PEL cell lines and xenografts. This effect is achieved through the perturbation of the cell cycle, the induction of rapid DNA damages and apoptosis, including the downregulation of the HHV-8 viral oncogenes.
Gianninò V. et al. (Etna Biotech, Catania, Italy, Cadila Helthcare Ltd., Ahmedabad, India): Evaluation of Immunogenicity Elicited by Recombinant Measles-Vectored HPV L1 Vaccine n Non-Human Primates
Persistent infections of oncogenic high-risk Human papillomaviruses is one of the main cause of development of cervical cancer. Widespread adoption of prophylactic HPV vaccination represents an important opportunity to prevent cervical cancer, particularly in developing countries, but first-generation of commercial HPV vaccines are expensive to produce and deliver. In her work, Gianninò developed an alternative HPV recombinant L1 vaccine, based on a live attenuated Measles virus (MV) vector platform. Live attenuated Edmoston Zagreb strain of MV is used as viral vector to carry HPV16L1 and HPV18L1 capsid proteins. MVEZ-HPV ability to induce immune response was assayed first in mice and subsequently in monkey, in comparison to commercial HPV vaccine, and it was found to be comperable.
Esaki S. et al. (Nagoya City University Graduate School of Medical Sciences and Medical School, Nagoya, Japan): Oncolytic Activity of HF10, a Naturally-Attenuated HSV-1 for Head And Neck Squamous Cell Carcinoma (HNSCC)
HF10 is a spontaneously generated, highly attenuated, HSV-1 laboratory strain. Shiniki and his group investigated the therapeutic potential of HF10 to HNSCC in vitro and in vivo. Several murine and human squamous carcinoma cell lines as well as a murine model for HNSCC have been generated in order to study the oncoloytic properties of HF10. The obtained results indicate: HF10 (1) replicates in tumor cells and induces necrosis, (2) decreases the tumor burden and prolongs the survival in the murine model, and (3) induces anti-tumor immunity.
Delaunay T. et al. (Université de Nantes, CHU de Nantes, Nantes, France): Sensitivity of Pleural Mesothelioma to Oncolytic Measles Virus Depends on Defect of the Type I IFN Response
Malignant Pleural Mesothelioma (MPM) is an aggressive cancer of the pleura. Delaunay presented an in vitro preclinical study on 22 MPM cell lines using oncolytic immunotherapy with live attenuated Schwarz strain of Measles Virus (MV), which replicates preferentially in tumor cells. 70% of tumor cells that are sensitive to MV replication are also unable to mount a type I IFN response, in contrast to control or resistant tumor cells. These data were confirmed by a transcriptomic study.
Ammour Y. et al. (Mechnikov Research Institute for Vaccines and Sera, Dimitry Rogachev Center for Pediatric Hematology, Oncology and Immunology, Engelhardt Institute of Molecular Biology, Moscow, Russia): Evaluation of Attenuated Strains L-16 of Measles Virus and L-3 of Mumps Virus as Potential Oncoloytic Agents Against Pediatric Acute Leukemia
This group evaluated the efficacy of attenuated measles virus vaccine strain L16 and the attenuated mumps virus vaccine strain L-3 against six primary acute B-lineage lymphoblastic cell lines. Cell survival was assessed by MTT test, luminescence assay and Real time to analyze fusion gene expression levels in cancer cells. The classical cytopathic effects of both viruses were observed at 72 h p.i. almost in all cells. Measles virus was able to eliminate completely lymphoblastic cells in five days whereas mups virus didn’t. Myeloid cells were affected only by combination of two viruses. Measles virus vaccine strain L-16 in combination with mumps virus vaccine strain L-3 were highly effective ageinst pediatric acute lymphoblastic leukemia and against acute myeloid leukemia.
Oded D. et al. (Tel Aviv University, Tel Aviv, Israel): Combined Genetic and Epigenetic Interferences with Interferon Signaling Expose Prostate Cancer Cells to Viral Function
Prostate cancer cell lines show high frequency of ISG methylation suggesting the negative regulation of IFN signaling by epigenetics. This allows the tumor to overcome the anti-tumorigenic effect of IFNs. In this cellular contest, oncolytic viruses are able to infect tumor cells more readily. This group studied the genetic and epigenetic mechanisms of interference with JAK/STAT signaling and their contribution to viral susceptibility of prostate cancer cells. Analysis of LNCaP cell line, known to be IFN insensitive, showed epigenetic modifications involving the IFN response and also bi-allelic inactivating mutation in JAK1 protein in exon 5 and 9. Epigenetic modifiers, like HDAC, can restore a low level of IFN signaling, block cell proliferation and reduce, without blocking, the infection of hMPV and EHDV-TAU. The combination of oncolysis and epigenetic modifiers can be useful tools for treatment of prostate cancer defective for JAK expression and IFN signaling.
Javed A. et al. (National University of Science and Technology, Att-ur-Rahman School of Applied Biosciences, Islamabad, Pakistan): Characterization and Oncolytic Potential Evaluation of Pakistani Newcastle Disease Virus Strain (NDV)
Newcastle disease is a contagious bird disease. Exposure of humans to infected birds can cause mild conjunctivitis and influenca-like symptoms, but the NDV otherwise poses no hazard to human health. Interst in the use of NDV as an anticancer agent has arisen from the ability of the virus to selectively kill human tumor cells with limited toxicity to normal cells. In this study the author evaluated the oncolytic potential of Pakistani strain of Newcastle disease virus. The virus was adapted to grow in hepatocarcinoma cell cline Huh 7. The results indicate that adapted virus induces apoptosis in Huh 7 with cytopathic effect, including plaque, and syncytium formations. Thus the virus shows an oncolytic potential to Huh 7 cells and therefore might be a good candidate for treatment of hepatocellular carcinoma.
News and Updates
Pre-Election to the Advisory Council 2016
In the period from June 21 to July 04, 2016, the full and corporate members of the Society were asked to pre-elect the 12 representatives of the Advisory Council of the European Society for Virology for the next term of office. In advance, 29 of the eligible full members had expressed their willingness to run as candidate and thus had been put on the ballot list for the pre-election to the Advisory Council.
The pre-elections gave a clear result. The voting participation was with a response rate of 46.5%. The following 12 members received the most votes and are thus pre-elected as Members to the Advisory Council (in alphabetical order):
- Albert Bosch, Department of Microbiology, University of Barcelona, Spain
- Margarita Del Val, Centro de Biología Molecular Severo Ochoa, Universidad Autònoma de Madrid, Campus de Cantoblanco, Spain
- W. Paul Duprex, Cell and Tissue Imaging Core, Dept. of Microbiology, Boston University School of Medicine, USA
- Urs Greber, Institute of Molecular Life Sciences, University of Zurich, Switzerland
- Marion Koopmans, Erasmus MC Rotterdam, The Netherlands
- Thomas Mertens, Institute for Virology, University Hospital of Ulm, Germany
- Thomas Mettenleiter, Department of Molecular Biology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Germany
- Albert Osterhaus, Department of Virology, Erasmus MC, The Netherlands
- Lennart Svensson, Div. of Molecular Virology, Med. Faculty, University of Linköping, Sweden
- Jan Svoboda, Dept. of Viral and Cellular Genetics, Institute of Molecular Genetics, Czech Republic
- Veronika von Messling, Paul-Ehrlich-Institut, Langen, Germany
- Dana Wolf, Clinical Virology Unit, Hadassah University Hospital, Israel
We thank the pre-elected members for accepting to serve in this council.
In case one of the pre-elected 12 members of the Advisory Council is elected to the Executive Board later on, the candidate who has received the next highest number of votes will succeed to the Advisory Council.
Pre-Election to President 2016
After the pre-election to the Advisory Council had been finalized, the full and corporate members of the Society were asked to pre-elect the President of the European Society for Virology for the next term of office. The pre-elected Advisory Council had proposed and approved President Giorgio Palù as candidate for the next Presidency 2016-2019 of the European Society for Virology, and the electorate had been asked to vote “yes” or “no” for Giorgio Palù as President.
Pre-elections were held in the period from July 12 to July 25, 2016, with a response rate of 50.8%. Prof. Giorgio Palù was confirmed by an overwhelming majority as President of the European Society for Virology 2016-2019.
Pre-Election to the Executive Board 2016
As a third step of the elections 2016, all full and corporate members of the Society will be asked to elect the representatives of the Executive Board for the next term of office. Here is an overview of the dates and procedures:
September 05-September 12, 2016: Nomination of candidates and approval by the newly elected Advisory Council
September 19-October 04, 2016: Pre-election to the Executive Board
The results of all pre-elections have to be confirmed in the course of the 4th General Assembly on October 21, 2016 during the 6th European Congress of Virology in Hamburg, Germany.
4th General Assembly of the European Society for Virology
21 October 2016
During ESV’s 4th General Assembly, final elections to the Advisory Council, President, and Executive Board will be held. Further topics will be, amongst others, an amendment of the ESV statutes and the election of Committee Chairpersons. Invitations will be sent to all members by e-mail and regular mail in September.
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Each member is appreciated by us. But it is not always possible to bring the address and e-mail data of all our members up to date. We are not able to invite you to the Society’s General Assembly, to send upcoming newsletters and requests for payment of membership fees, or to provide you with any other information when your address data have changed
Please just send an e-mail to email@example.com for any update.
3rd Innovative Approaches for Identification of Antiviral Agents Summer School
29 September – 2 October, 2016
Santa Margherita di Pula, Italy
This Summer School aims to provide an informal and interactive environment to review the application of high throughput screening techniques to identification of novel and clinically-significant antiviral drugs. The Summer School is targeted to researchers at an early stage in their career, combining examples of drug discovery from internationally-recognized experts in the field with informal, small-group thematic discussion sessions. Evening sessions will allow students to present their work in the form of either a poster or oral presentations and receive feedback from their colleagues.
6th European Congress of Virology
19 – 22 October, 2016
The European Congress of Virology (ECV) is the premier virology conference in Europe and is organized by the European Society for Virology. ECV2016 will bring together both junior and senior scientists, and will cover all aspects of virus research including basic, clinical, veterinary and plant virology.
Please see http://www.eurovirology2016.eu/ for more information.
Further Conferences and Events of Interest
Within Host RNA Virus Persistence: Mechanisms and Consequences
24 – 26 August, 2016
St Andrews, Scotland
EUROPIC 2016 – Conference of the European Study Group of Picornaviruses
04 – 08 September, 2016
Les Diablerets, Switzerland
Frontiers of Retrovirology 2016 – Complex Retroviruses, Retroelements and Their Hosts
12 – 14 September, 2016
Erlangen, Germany www.frontiers-of-retrovirology.com
Please feel free to contact us should you have any suggestions and ideas for the upcoming newsletters: firstname.lastname@example.org