21 results on '"Oncolytic viruse"'
Search Results
2. Artificially cloaked viral nanovaccine for cancer immunotherapy
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Flavia Fontana, Harri Alenius, Leena Ylösmäki, Hélder A. Santos, Beatriz Martins, Cristian Capasso, Vincenzo Cerullo, Jouni Hirvonen, Arto Urtti, Otto K. Kari, Firas Hamdan, Manlio Fusciello, Erkko Ylösmäki, Sara Feola, Jacopo Chiaro, Siri Tähtinen, Karita Peltonen, Joseph Ndika, ImmunoViroTherapy Lab, Division of Pharmaceutical Biosciences, Drug Research Program, Digital Precision Cancer Medicine (iCAN), Nanomedicines and Biomedical Engineering, Division of Pharmaceutical Chemistry and Technology, Drug Delivery Unit, Department of Bacteriology and Immunology, Medicum, HUMI - Human Microbiome Research, Drug Delivery, Jouni Hirvonen / Principal Investigator, Helsinki One Health (HOH), Helsinki Institute of Life Science HiLIFE, Fusciello, M., Fontana, F., Tahtinen, S., Capasso, C., Feola, S., Martins, B., Chiaro, J., Peltonen, K., Ylosmaki, L., Ylosmaki, E., Hamdan, F., Kari, O. K., Ndika, J., Alenius, H., Urtti, A., Hirvonen, J. T., Santos, H. A., and Cerullo, V.
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0301 basic medicine ,medicine.medical_treatment ,General Physics and Astronomy ,Cancer immunotherapy ,02 engineering and technology ,Injections, Intralesional ,T-CELL THERAPY ,Mice ,Nanoparticle ,oncoimmunology ,Neoplasms ,NANOPARTICLES ,Medicine ,lcsh:Science ,IN-VIVO ,Multidisciplinary ,318 Medical biotechnology ,Melanoma ,021001 nanoscience & nanotechnology ,SOLID TUMORS ,3. Good health ,Oncolytic Viruses ,CO-DELIVERY ,oncolytic vaccines ,Treatment Outcome ,317 Pharmacy ,VACCINATION ,Female ,immunotherapy ,0210 nano-technology ,Cancer Vaccine ,Human ,Science ,ANTIGEN ,Drug development ,Oncolytic Viruse ,Cancer Vaccines ,GENE-TRANSFER ,Article ,General Biochemistry, Genetics and Molecular Biology ,OVARIAN-CANCER ,Adenoviridae ,ADENOVIRUS ,03 medical and health sciences ,Immune system ,Antigen ,Antigens, Neoplasm ,Cell Line, Tumor ,Animals ,Humans ,oncolytic virus ,business.industry ,Animal ,Cell Membrane ,Cancer ,General Chemistry ,Immunotherapy ,medicine.disease ,Xenograft Model Antitumor Assays ,Oncolytic virus ,Disease Models, Animal ,030104 developmental biology ,biohybrid nanoparticles ,Cancer research ,Neoplasm ,lcsh:Q ,business ,Ovarian cancer - Abstract
Virus-based cancer vaccines are nowadays considered an interesting approach in the field of cancer immunotherapy, despite the observation that the majority of the immune responses they elicit are against the virus and not against the tumor. In contrast, targeting tumor associated antigens is effective, however the identification of these antigens remains challenging. Here, we describe ExtraCRAd, a multi-vaccination strategy focused on an oncolytic virus artificially wrapped with tumor cancer membranes carrying tumor antigens. We demonstrate that ExtraCRAd displays increased infectivity and oncolytic effect in vitro and in vivo. We show that this nanoparticle platform controls the growth of aggressive melanoma and lung tumors in vivo both in preventive and therapeutic setting, creating a highly specific anti-cancer immune response. In conclusion, ExtraCRAd might serve as the next generation of personalized cancer vaccines with enhanced features over standard vaccination regimens, representing an alternative way to target cancer., Cancer therapy using oncolytic virus has shown pre-clinical and clinical efficacy. Here, the authors report ExtraCRAd, an oncolytic virus cloaked with tumour cell membrane and report its therapeutic effects in vitro and in vivo in multiple mouse tumour models.
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- 2019
3. Novel oncolytic adenovirus expressing enhanced cross-hybrid IgGA Fc PD-L1 inhibitor activates multiple immune effector populations leading to enhanced tumor killing in vitro, in vivo and with patient-derived tumor organoids
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Hamdan, Firas, Ylösmäki, Erkko, Chiaro, Jacopo, Giannoula, Yvonne, Long, Maeve, Fusciello, Manlio, Feola, Sara, Martins, Beatriz, Feodoroff, Michaela, Antignani, Gabriella, Russo, Salvatore, Kari, Otto, Lee, Moon, Järvinen, Petrus, Nisen, Harry, Kreutzman, Anna, Leusen, Jeanette, Mustjoki, Satu, McWilliams, Thomas G., Grönholm, Mikaela, Cerullo, Vincenzo, Hamdan, F., Ylosmaki, E., Chiaro, J., Giannoula, Y., Long, M., Fusciello, M., Feola, S., Martins, B., Feodoroff, M., Antignani, G., Russo, S., Kari, O., Lee, M., Jarvinen, P., Nisen, H., Kreutzman, A., Leusen, J., Mustjoki, S., Mcwilliams, T. G., Gronholm, M., Cerullo, V., Division of Pharmaceutical Biosciences, Drug Research Program, ImmunoViroTherapy Lab, Drug Delivery, TRIMM - Translational Immunology Research Program, STEMM - Stem Cells and Metabolism Research Program, Department of Anatomy, Medicum, Institute for Molecular Medicine Finland, Research Services, Drug Delivery Unit, HUS Abdominal Center, HUSLAB, HUS Comprehensive Cancer Center, Department of Clinical Chemistry and Hematology, Digital Precision Cancer Medicine (iCAN), Research Programs Unit, Faculty of Medicine, and Biosciences
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Organoid ,BLOCKADE ,Immune Checkpoint Inhibitor ,3122 Cancers ,Oncolytic Viruse ,GAMMA-RS ,Mice, SCID ,Receptors, Fc ,THERAPY ,Adenoviridae ,Mice ,Mice, Inbred NOD ,Cell Line, Tumor ,NEUTROPHILS ,Oncolytic Virotherapy ,RECEPTOR ,Animal ,EFFICACY ,antibody formation ,CANCER ,Immunoglobulin A ,ANTIBODY ,317 Pharmacy ,REPLICATION ,T-CELLS ,1182 Biochemistry, cell and molecular biology ,Neoplasm ,Female ,Immunotherapy ,Human - Abstract
Background Despite the success of immune checkpoint inhibitors against PD-L1 in the clinic, only a fraction of patients benefit from such therapy. A theoretical strategy to increase efficacy would be to arm such antibodies with Fc-mediated effector mechanisms. However, these effector mechanisms are inhibited or reduced due to toxicity issues since PD-L1 is not confined to the tumor and also expressed on healthy cells. To increase efficacy while minimizing toxicity, we designed an oncolytic adenovirus that secretes a cross-hybrid Fc-fusion peptide against PD-L1 able to elicit effector mechanisms of an IgG1 and also IgA1 consequently activating neutrophils, a population neglected by IgG1, in order to combine multiple effector mechanisms. Methods The cross-hybrid Fc-fusion peptide comprises of an Fc with the constant domains of an IgA1 and IgG1 which is connected to a PD-1 ectodomain via a GGGS linker and was cloned into an oncolytic adenovirus. We demonstrated that the oncolytic adenovirus was able to secrete the cross-hybrid Fc-fusion peptide able to bind to PD-L1 and activate multiple immune components enhancing tumor cytotoxicity in various cancer cell lines, in vivo and ex vivo renal-cell carcinoma patient-derived organoids. Results Using various techniques to measure cytotoxicity, the cross-hybrid Fc-fusion peptide expressed by the oncolytic adenovirus was shown to activate Fc-effector mechanisms of an IgA1 (neutrophil activation) as well as of an IgG1 (natural killer and complement activation). The activation of multiple effector mechanism simultaneously led to significantly increased tumor killing compared with FDA-approved PD-L1 checkpoint inhibitor (Atezolizumab), IgG1-PDL1 and IgA-PDL1 in various in vitro cell lines, in vivo models and ex vivo renal cell carcinoma organoids. Moreover, in vivo data demonstrated that Ad-Cab did not require CD8+ T cells, unlike conventional checkpoint inhibitors, since it was able to activate other effector populations. Conclusion Arming PD-L1 checkpoint inhibitors with Fc-effector mechanisms of both an IgA1 and an IgG1 can increase efficacy while maintaining safety by limiting expression to the tumor using oncolytic adenovirus. The increase in tumor killing is mostly attributed to the activation of multiple effector populations rather than activating a single effector population leading to significantly higher tumor killing.
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- 2021
4. Generation of a retargeted oncolytic herpes virus encoding adenosine deaminase for tumor adenosine clearance
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Chiara Gentile, Arianna Finizio, Guendalina Froechlich, Anna Morena D’Alise, Gabriella Cotugno, Sara Amiranda, Alfredo Nicosia, Elisa Scarselli, Nicola Zambrano, Emanuele Sasso, Gentile, C., Finizio, A., Froechlich, G., D'Alise, A. M., Cotugno, G., Amiranda, S., Nicosia, A., Scarselli, E., Zambrano, N., and Sasso, E.
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THP-1 Cell ,Adenosine ,QH301-705.5 ,Adenosine Deaminase ,Oncolytic Viruse ,Catalysis ,Cell Line ,Inorganic Chemistry ,Targeted therapy ,Antigens, CD ,Tumor Microenvironment ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,Herpesviridae ,oncolytic virus ,Oncolytic Virotherapy ,Immunometabolism ,Organic Chemistry ,Oncolytic viru ,General Medicine ,Computer Science Applications ,Chemistry ,adenosine ,adenosine deaminase ,targeted therapy ,immunometabolism ,immunotherapy ,Neoplasm ,Immunotherapy ,Human - Abstract
Background: Oncolytic viruses are immunotherapeutic agents that can be engineered to encode payloads of interest within the tumor microenvironment to enhance therapeutic efficacy. Their therapeutic potential could be limited by many avenues for immune evasion exerted by the tumor. One such is mediated by adenosine, which induces pleiotropic immunosuppression by inhibiting antitumor immune populations as well as activating tolerogenic stimuli. Adenosine is produced starting from the highly immunostimulatory ATP, which is progressively hydrolyzed to ADP and adenosine by CD39 and CD73. Cancer cells express high levels of CD39 and CD73 ectoenzymes, thus converting immunostimulatory purinergic signal of ATP into an immunosuppressive signal. For this reason, CD39, CD73 and adenosine receptors are currently investigated in clinical trials as targets for metabolic cancer immunotherapy. This is of particular relevance in the context of oncovirotherapy, as immunogenic cell death induced by oncolytic viruses causes the secretion of a high amount of ATP which is available to be quickly converted into adenosine. Methods: Here, we took advantage of adenosine deaminase enzyme that naturally converts adenosine into the corresponding inosine derivative, devoid of immunoregulatory function. We encoded ADA into an oncolytic targeted herpes virus redirected to human HER2. An engineered ADA with an ectopic signal peptide was also generated to improve enzyme secretion (ADA-SP). Results: Insertion of the expression cassette was not detrimental for viral yield and cancer cell cytotoxicity. The THV_ADA and THV_ADA-SP successfully mediated the secretion of functional ADA enzyme. In in vitro model of human monocytes THP1, this ability of THV_ADA and THV_ADA-SP resulted in the retrieval of eADO-exposed monocytes replication rate, suggesting the proficiency of the viruses in rescuing the immune function. Conclusions: Encoding ADA into oncolytic viruses revealed promising properties for preclinical exploitation.
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- 2021
5. Virotherapy: From single agents to combinatorial treatments
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Sarah Di Somma, Carmelina Antonella Iannuzzi, Francesca Pentimalli, Giuseppe Portella, Anna Maria Malfitano, Malfitano, A. M., Di Somma, S., Iannuzzi, C. A., Pentimalli, F., and Portella, G.
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0301 basic medicine ,Alkylating Agents ,Antimetabolites, Antineoplastic ,medicine.drug_class ,Topoisomerase Inhibitors ,medicine.medical_treatment ,Protein Kinase Inhibitor ,Platinum Compounds ,Oncolytic Viruse ,Topoisomerase Inhibitor ,Antimitotic Agents ,Platinum Compound ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Histone Deacetylase Inhibitor ,Tumor Microenvironment ,Medicine ,Humans ,Virotherapy ,Protein Kinase Inhibitors ,Pharmacology ,Oncolytic Virotherapy ,Antibiotics, Antineoplastic ,business.industry ,Cancer ,Oncolytic viru ,Antibodies, Monoclonal ,Immunotherapy ,Proteasome complex ,medicine.disease ,Alkylating Agent ,Combined Modality Therapy ,Oncolytic virus ,Histone Deacetylase Inhibitors ,Oncolytic Viruses ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Antimitotic Agent ,Cancer research ,Immunogenic cell death ,Neoplasm ,business ,Topoisomerase inhibitor ,Human - Abstract
Virotherpay is emerging as a promising strategy against cancer, and three oncolytic viruses (OVs) have gained approval in different countries for the treatment of several cancer types. Beyond the capability to selectively infect, replicate and lyse cancer cells, OVs act through a multitude of events, including modification of the tumour micro/macro-environment as well as a complex modulation of the anti-tumour immune response by activation of danger signals and immunogenic cell death pathways. Most OVs show limited effects, depending on the viral platform and the interactions with the host. OVs used as monotherapy only in a minority of patients elicited a full response. Better outcomes were obtained using OVs in combination with other treatments, such as immune therapy or chemotherapy, suggesting that the full potential of OVs can be unleashed in combination with other treatment modalities. Here, we report the main described combination of OVs with conventional chemotherapeutic agents: platinum salts, mitotic inhibitors, anthracyclines and other antibiotics, anti-metabolites, alkylating agents and topoisomerase inhibitors. Additionally, our work provides an overview of OV combination with targeted therapies: histone deacetylase inhibitors, kinase inhibitors, monoclonal antibodies, inhibitors of DNA repair, inhibitors of the proteasome complex and statins that demonstrated enhanced OV anti-neoplastic activity. Although further studies are required to assess the best combinations to translate the results in the clinic, it is clear that combined therapies, acting with complementary mechanisms of action might be useful to target cancer lesions resistant to currently available treatments.
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- 2020
6. United virus: The oncolytic tag-team against cancer!
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Le Bœuf, Fabrice and Bell, John C.
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CANCER treatment , *METASTASIS , *DISEASE progression , *VACCINIA , *VESICULAR stomatitis , *MEDICAL care - Abstract
Abstract: There is an urgent need for innovative therapeutic strategies to treat aggressive metastatic cancers that are incurable with standard therapeutic approaches. Novel treatment strategies like oncolytic virotherapy have led, in some cases, to impressive effects on disease progression in human trials, suggesting that approval of an oncolytic virus therapeutic is on the horizon. While combinations of oncolytic viruses with small molecules are already being tested and have shown promise, we propose that even greater therapeutic synergies could be achieved through rational design of complementary virus therapeutics. In this review, we discuss rational chemical and biological combination strategies to enhance oncolytic virotherapy highlighting the promising combination of vaccinia and vesicular stomatitis oncolytic viruses. [Copyright &y& Elsevier]
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- 2010
- Full Text
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7. Poly-Gamma-Glutamic Acid (γ-PGA)-Based Encapsulation of Adenovirus to Evade Neutralizing Antibodies
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Mariastella Scandola, Marek Kowalczuk, Iza Radecka, Angel L. Armesilla, Abhishek Gupta, Maria Letizia Focarete, Barbara Mendrek, Ibrahim R Khalil, Tamara Khalaf, Martin Khechara, Sathishkumar Kurusamy, Khalil, Ibrahim R, Khechara, Martin P, Kurusamy, Sathishkumar, Armesilla, Angel L, Gupta, Abhishek, Mendrek, Barbara, Khalaf, Tamara, Scandola, Mariastella, Focarete, Maria Letizia, Kowalczuk, Marek, and Radecka, Iza
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0301 basic medicine ,Polymers ,Pharmaceutical Science ,immunogenicity ,Ligands ,medicine.disease_cause ,Analytical Chemistry ,chemistry.chemical_compound ,Nanoparticle ,Neoplasms ,Drug Discovery ,Polymer ,Neutralizing antibody ,Drug Carrier ,Oncolytic Virotherapy ,Drug Carriers ,Immunity, Cellular ,biology ,Chemistry ,PGA ,adenovirus ,Controlled release ,Oncolytic Viruses ,Polyglutamic Acid ,Chemistry (miscellaneous) ,Adenoviru ,Molecular Medicine ,Drug carrier ,Human ,γ-PGA ,Ligand ,Oncolytic Viruse ,Article ,Adenoviridae ,Viral vector ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,medicine ,Humans ,Physical and Theoretical Chemistry ,Organic Chemistry ,Polyglutamic acid ,biodegradable polymer ,Antibodies, Neutralizing ,Biodegradable polymer ,Oncolytic virus ,030104 developmental biology ,biology.protein ,Biophysics ,Nanoparticles ,Neoplasm ,chitosan - Abstract
In recent years, there has been an increasing interest in oncolytic adenoviral vectors as an alternative anticancer therapy. The induction of an immune response can be considered as a major limitation of this kind of application. Significant research efforts have been focused on the development of biodegradable polymer poly-gamma-glutamic acid (&gamma, PGA)-based nanoparticles used as a vector for effective and safe anticancer therapy, owing to their controlled and sustained-release properties, low toxicity, as well as biocompatibility with tissue and cells. This study aimed to introduce a specific destructive and antibody blind polymer-coated viral vector into cancer cells using &gamma, PGA and chitosan (CH). Adenovirus was successfully encapsulated into the biopolymer particles with an encapsulation efficiency of 92% and particle size of 485 nm using the ionic gelation method. Therapeutic agents or nanoparticles (NPs) that carry therapeutics can be directed specifically to cancerous cells by decorating their surfaces using targeting ligands. Moreover, in vitro neutralizing antibody response against viral capsid proteins can be somewhat reduced by encapsulating adenovirus into &gamma, PGA-CH NPs, as only 3.1% of the encapsulated adenovirus was detected by anti-adenovirus antibodies in the presented work compared to naked adenoviruses. The results obtained and the unique characteristics of the polymer established in this research could provide a reference for the coating and controlled release of viral vectors used in anticancer therapy.
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- 2018
- Full Text
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8. Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the dl922-947 Oncolytic Virus in Malignant Mesothelioma Cell Lines
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Anna Maria Malfitano, Martina Bruno, Paola Indovina, Antonio Giordano, Iris Maria Forte, Francesca Pentimalli, Giuseppe Portella, Sarah Di Somma, Carmelina Antonella Iannuzzi, Iannuzzi, C. A., Indovina, P., Forte, I. M., Somma, S. D., Malfitano, A. M., Bruno, M., Portella, G., Pentimalli, F., and Giordano, A.
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0301 basic medicine ,Cell Cycle Proteins ,DNA damage response ,lcsh:Chemistry ,0302 clinical medicine ,Protein-Tyrosine Kinase ,Cell Cycle Protein ,Phosphorylation ,Dl922-947 ,lcsh:QH301-705.5 ,Spectroscopy ,Oncolytic Virotherapy ,biology ,Chemistry ,Kinase ,apoptosis ,General Medicine ,Protein-Tyrosine Kinases ,oncolytic adenovirus ,Computer Science Applications ,Oncolytic Viruses ,Wee1 ,Oncolytic adenoviru ,030220 oncology & carcinogenesis ,malignant mesothelioma ,Adavosertib ,Human ,Oncolytic adenovirus ,Programmed cell death ,Cell Survival ,Protein Kinase Inhibitor ,Asbesto ,Oncolytic Viruse ,Pyrimidinones ,Article ,Catalysis ,Adenoviridae ,Inorganic Chemistry ,03 medical and health sciences ,Cell Line, Tumor ,Humans ,WEE1 ,Physical and Theoretical Chemistry ,Protein Kinase Inhibitors ,Molecular Biology ,G2/M checkpoint ,Cyclin-dependent kinase 1 ,Mesothelioma, Malignant ,Organic Chemistry ,Apoptosi ,Asbestos ,G2-M DNA damage checkpoint ,Oncolytic virus ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,dl922-947 ,MK-1775 ,Apoptosis ,Pyrazole ,AZD1775 ,biology.protein ,Cancer research ,Pyrazoles ,DNA Damage - Abstract
Malignant mesothelioma (MM) is a very aggressive asbestos-related cancer, for which no therapy proves to be effective. We have recently shown that the oncolytic adenovirus dl922-947 had antitumor effects in MM cell lines and murine xenografts. Previous studies demonstrated that dl922-947-induced host cell cycle checkpoint deregulation and consequent DNA lesions associated with the virus efficacy. However, the cellular DNA damage response (DDR) can counteract this virus action. Therefore, we assessed whether AZD1775, an inhibitor of the G2/M DNA damage checkpoint kinase WEE1, could enhance MM cell sensitivity to dl922-947. Through cell viability assays, we found that AZD1775 synergized with dl922-947 selectively in MM cell lines and increased dl922-947-induced cell death, which showed hallmarks of apoptosis (annexinV-positivity, caspase-dependency, BCL-XL decrease, chromatin condensation). Predictably, dl922-947 and/or AZD1775 activated the DDR, as indicated by increased levels of three main DDR players: phosphorylated histone H2AX (&gamma, H2AX), phospho-replication protein A (RPA)32, phospho-checkpoint kinase 1 (CHK1). Dl922-947 also increased inactive Tyr-15-phosphorylated cyclin-dependent kinase 1 (CDK1), a key WEE1 substrate, which is indicative of G2/M checkpoint activation. This increase in phospho-CDK1 was effectively suppressed by AZD1775, thus suggesting that this compound could, indeed, abrogate the dl922-947-induced DNA damage checkpoint in MM cells. Overall, our data suggest that the dl922-947-AZD1775 combination could be a feasible strategy against MM.
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- 2020
9. New Insights into Parvovirus Research
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Giorgio Gallinella and Gallinella G.
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Viral metagenomics ,Carnivore protoparvovirus 1 ,Agricultural pest ,parvoviru ,Parvoviridae Infections ,Structure-Activity Relationship ,antivirals ,Virology ,Drug Discovery ,Antibody Interactions ,Animals ,Humans ,structural biology ,genetics ,Sociology ,Erythroid Progenitor Cells ,Family Parvoviridae ,biology ,Parvovirus ,Research ,parvovirus ,Acute gastroenteritis ,biology.organism_classification ,antiviral ,Data science ,Editorial ,oncolytic viruse ,Infectious Diseases ,oncolytic viruses ,Disease Susceptibility ,genetic - Abstract
The family Parvoviridae includes an ample and most diverse collection of viruses. Exploring the biological diversity and the inherent complexity in these apparently simple viruses has been a continuous commitment for the scientific community since their first discovery more than fifty years ago. The Special Issue of ‘Viruses’ dedicated to the ‘New Insights into Parvovirus Research’ aimed at presenting a ‘state of the art’ in many aspects of research in the field, at collecting the newest contributions on unresolved issues, and at presenting new approaches exploiting systemic (-omic) methodologies.
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- 2019
10. Constitutive Interferon Pathway Activation in Tumors as an Efficacy Determinant Following Oncolytic Virotherapy
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Suzanne Greiner, Ann L. Oberg, Caterina Giannini, Paul Haluska, Ianko D. Iankov, E. Aubrey Thompson, S. Keith Anderson, Evanthia Galanis, Alexey A. Leontovich, Cheyne Kurokawa, Jin Jen, Ian F. Parney, Jann N. Sarkaria, Mark E. Jentoft, Matthew J. Maurer, Mark A. Schroeder, Ileana Aderca, S. John Weroha, Marc A. Becker, Kurokawa C., Iankov I.D., Anderson S.K., Aderca I., Leontovich A.A., Maurer M.J., Oberg A.L., Schroeder M.A., Giannini C., Greiner S.M., Becker M.A., Thompson E.A., Haluska P., Jentoft M.E., Parney I.F., Weroha S.J., Jen J., Sarkaria J.N., and Galanis E.
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0301 basic medicine ,Cancer Research ,Xenograft Model Antitumor Assay ,Genetic Vectors ,Reproducibility of Result ,Gene Expression ,Oncolytic Viruse ,Virus ,Measles virus ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Interferon ,Genes, Reporter ,Cell Line, Tumor ,Neoplasms ,medicine ,Animals ,Humans ,Oncolytic Virotherapy ,biology ,Animal ,Virus receptor ,Interferon-stimulated gene ,Reproducibility of Results ,Articles ,Gene signature ,biology.organism_classification ,Xenograft Model Antitumor Assays ,Oncolytic virus ,Gene expression profiling ,Disease Models, Animal ,Oncolytic Viruses ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Measles viru ,Cancer research ,Neoplasm ,Genetic Vector ,Interferons ,Human ,medicine.drug ,Signal Transduction - Abstract
Background Attenuated measles virus (MV) strains are promising agents currently being tested against solid tumors or hematologic malignancies in ongoing phase I and II clinical trials; factors determining oncolytic virotherapy success remain poorly understood, however. Methods We performed RNA sequencing and gene set enrichment analysis to identify pathways differentially activated in MV-resistant (n = 3) and -permissive (n = 2) tumors derived from resected human glioblastoma (GBM) specimens and propagated as xenografts (PDX). Using a unique gene signature we identified, we generated a diagonal linear discriminant analysis (DLDA) classification algorithm to predict MV responders and nonresponders, which was validated in additional randomly selected GBM and ovarian cancer PDX and 10 GBM patients treated with MV in a phase I trial. GBM PDX lines were also treated with the US Food and Drug Administration-approved JAK inhibitor, ruxolitinib, for 48 hours prior to MV infection and virus production, STAT1/3 signaling and interferon stimulated gene expression was assessed. All statistical tests were two-sided. Results Constitutive interferon pathway activation, as reflected in the DLDA algorithm, was identified as the key determinant for MV replication, independent of virus receptor expression, in MV-permissive and -resistant GBM PDXs. Using these lines as the training data for the DLDA algorithm, we confirmed the accuracy of our algorithm in predicting MV response in randomly selected GBM PDX ovarian cancer PDXs. Using the DLDA prediction algorithm, we demonstrate that virus replication in patient tumors is inversely correlated with expression of this resistance gene signature (ρ = -0.717, P = .03). In vitro inhibition of the interferon response pathway with the JAK inhibitor ruxolitinib was able to overcome resistance and increase virus production (1000-fold, P = .03) in GBM PDX lines. Conclusions These findings document a key mechanism of tumor resistance to oncolytic MV therapy and describe for the first time the development of a prediction algorithm to preselect for oncolytic treatment or combinatorial strategies.
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- 2018
11. Oncolytic vaccines increase the response to PD-L1 blockade in immunogenic and poorly immunogenic tumors
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Manlio Fusciello, Vincenzo Cerullo, F. Frascaro, Erkko Ylösmäki, Lucio Pastore, Karita Peltonen, Siri Tähtinen, Sara Carpi, M. Medeot, Cristian Capasso, Sara Feola, Beatriz Martins, Feola, S., Capasso, C., Fusciello, Celeste, Martins, B., Tähtinen, S., Medeot, M., Carpi, S., Frascaro, F., Ylosmäki, E., Peltonen, K., Pastore, L., and Cerullo, V.
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0301 basic medicine ,lcsh:Immunologic diseases. Allergy ,medicine.medical_treatment ,Immunology ,oncolytic vaccine ,therapeutic antibodies ,lcsh:RC254-282 ,03 medical and health sciences ,Immune system ,breast cancer ,therapeutic antibodie ,PD-L1 ,medicine ,melanoma ,Immunology and Allergy ,Triple-negative breast cancer ,Original Research ,biology ,cancer epitopes ,cancer vaccines ,checkpoint inhibitors ,immunotherapy ,oncolytic vaccines ,oncolytic viruses ,therapeutic vaccination ,Oncology ,business.industry ,Melanoma ,Immunotherapy ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immune checkpoint ,3. Good health ,Oncolytic virus ,030104 developmental biology ,checkpoint inhibitor ,oncolytic viruse ,Cancer research ,biology.protein ,Cancer vaccine ,cancer epitope ,business ,lcsh:RC581-607 ,cancer vaccine - Abstract
Activation of immune checkpoint pathways and limited T- cell infiltration result in immunological escape of tumors. Although immune checkpoint inhibitors are currently approved for several types of cancers, the response rate is often limited by the lack of tumor specific T-cells within the malignant tissue. Therefore, new combinatorial strategies are needed to enhance the clinical benefit of immune checkpoint inhibitors. We have previously developed PeptiCRAd, an oncolytic vaccine platform capable of directing the immune response toward tumor epitopes. In this study, we evaluated whether the platform could be used to increase the response rate to checkpoint inhibitors in both highly immunogenic and poorly immunogenic tumors, such as melanoma and triple negative breast cancer (TNBC). We report here that anti-PD-L1 therapy in combination with PeptiCRAd significantly reduced the growth of melanomas and increased the response rate to checkpoint inhibition. In fact, we registered a higher rate of complete responses among mice treated with the combination. This approach promoted the presence of non-exhausted antigen-specific T-cells within the tumor in comparison to anti-PD-L1 monotherapy. Furthermore, we found that targeting both MHC-I and II restricted tumor epitopes was necessary to decrease the growth of the poorly immunogenic TNBC model 4T1 and that combination with PD-L1 blockade increased the number of responders to checkpoint inhibition. Finally, the described strategy was validated in a translational in vitro model using HLA matched human PBMCs and tumor cell lines. Consistent to our previous results, improved cytotoxicity was observed with combination of PeptiCRAd and anti-PD-L1. These results demonstrate that oncolytic virus based cancer vaccine can significantly improve the response rate to checkpoint blocking antibodies in the context of immunogenic and non-immunogenic tumors.
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- 2018
12. A Strategy for Cultivation of Retargeted Oncolytic Herpes Simplex Viruses in Non-cancer Cells
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Biljana Petrovic, Alfredo Nicosia, Valentina Gatta, Costanza Casiraghi, Gabriella Campadelli-Fiume, Valerio Leoni, Leoni, Valerio, Gatta, Valentina, Casiraghi, Costanza, Nicosia, Alfredo, Petrovic, Biljana, Campadelli-Fiume, Gabriella, Leoni, V, Gatta, V, Casiraghi, C, Nicosia, A, Petrovic, B, and Campadelli-Fiume, G
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0301 basic medicine ,Virus Cultivation ,Receptor, ErbB-2 ,viruses ,Immunology ,Herpesvirus 1, Human ,medicine.disease_cause ,Microbiology ,Cell Line ,03 medical and health sciences ,Gene Delivery ,Virology ,HER2 ,Oncolytic viruse ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Simplexvirus ,Vero Cells ,Tropism ,retargeting ,Oncolytic Virotherapy ,biology ,HSV ,3. Good health ,Oncolytic virus ,Vero ,Oncolytic Viruses ,Viral Tropism ,030104 developmental biology ,Herpes simplex virus ,Cell culture ,Insect Science ,Cancer cell ,Tissue tropism ,biology.protein ,Vero cell ,Antibody ,Genetic Engineering - Abstract
The oncolytic herpes simplex virus (HSV) that has been approved for clinical practice and those HSVs in clinical trials are attenuated viruses, often with the neurovirulence gene γ 1 34.5 and additional genes deleted. One strategy to engineer nonattenuated oncolytic HSVs consists of retargeting the viral tropism to a cancer-specific receptor of choice, exemplified by HER2 (human epidermal growth factor receptor 2), which is present in breast, ovary, and other cancers, and in detargeting from the natural receptors. Because the HER2-retargeted HSVs strictly depend on this receptor for infection, the viruses employed in preclinical studies were cultivated in HER2-positive cancer cells. The production of clinical-grade viruses destined for humans should avoid the use of cancer cells. Here, we engineered the R-213 recombinant, by insertion of a 20-amino-acid (aa) short peptide (named GCN4) in the gH of R-LM113; this recombinant was retargeted to HER2 through insertion in gD of a single-chain antibody (scFv) to HER2. Next, we generated a Vero cell line expressing an artificial receptor (GCN4R) whose N terminus consists of an scFv to GCN4 and therefore is capable of interacting with GCN4 present in gH of R-213. R-213 replicated as well as R-LM113 in SK-OV-3 cells, implying that addition of the GCN4 peptide was not detrimental to gH. R-213 grew to relatively high titers in Vero-GCN4R cells, efficiently spread from cell to cell, and killed both Vero-GCN4R and SK-OV-3 cells, as expected for an oncolytic virus. Altogether, Vero-GCN4R cells represent an efficient system for cultivation of retargeted oncolytic HSVs in non-cancer cells. IMPORTANCE There is growing interest in viruses as oncolytic agents, which can be administered in combination with immunotherapeutic compounds, including immune checkpoint inhibitors. The oncolytic HSV approved for clinical practice and those in clinical trials are attenuated viruses. An alternative to attenuation is a cancer specificity achieved by tropism retargeting to selected cancer receptors. However, the retargeted oncolytic HSVs strictly depend on cancer receptors for infection. Here, we devised a strategy for in vitro cultivation of retargeted HSVs in non-cancer cells. The strategy envisions a double-retargeting approach: one retargeting is via gD to the cancer receptor, and the second retargeting is via gH to an artificial receptor expressed in Vero cells. The double-retargeted HSV uses alternatively the two receptors to infect cancer cells or producer cells. A universal non-cancer cell line for growth of clinical-grade retargeted HSVs represents a step forward in the translational phase.
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- 2017
13. Armed Oncolytic Virus Enhances Immune Functions of Chimeric Antigen Receptor–Modified T Cells in Solid Tumors
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Iulia Diaconu, Gianpietro Dotti, Vincenzo Cerullo, Hao Liu, Ignazio Caruana, Barbara Savoldo, Nobuhiro Nishio, Valentina Hoyos, Lisa Bouchier-Hayes, Nishio, Nobuhiro, Diaconu, Iulia, Liu, Hao, Cerullo, Vincenzo, Caruana, Ignazio, Hoyos, Valentina, Bouchier-Hayes, Lisa, Savoldo, Barbara, and Dotti, Gianpietro
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Cancer Research ,Xenograft Model Antitumor Assay ,T-Lymphocytes ,medicine.medical_treatment ,Receptors, Antigen, T-Cell ,Oncolytic Viruse ,Biology ,Article ,Mice ,Neuroblastoma ,Immune system ,Antigen ,Mice, Inbred NOD ,Cell Line, Tumor ,medicine ,Animals ,Cytotoxic T cell ,Antigen-presenting cell ,Cytokine ,Oncolytic Virotherapy ,Microscopy, Confocal ,Animal ,Immunotherapy ,Xenograft Model Antitumor Assays ,Chimeric antigen receptor ,Tumor antigen ,3. Good health ,Oncolytic virus ,Oncolytic Viruses ,Disease Models, Animal ,T-Lymphocyte ,Oncology ,Immunology ,Cancer research ,Cytokines - Abstract
The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors. Cancer Res; 74(18); 5195–205. ©2014 AACR.
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- 2014
14. CD40 ligand and tdTomato-armed vaccinia virus for induction of antitumor immune response and tumor imaging
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Iulia Diaconu, Vincenzo Cerullo, A. Karttunen, Markus Vähä-Koskela, Marko Ahonen, Suvi Parviainen, Mari Hirvinen, Akseli Hemminki, Parviainen, S., Ahonen, M., Diaconu, I., Hirvinen, M., Karttunen, A., Vähä-Koskela, M., Hemminki, A., and Cerullo, V.
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Xenograft Model Antitumor Assay ,medicine.medical_treatment ,CD40 Ligand ,Genetic Vectors ,Oncolytic Viruse ,Antineoplastic Agents ,Apoptosis ,Biology ,Virus ,Antineoplastic Agent ,Mice ,chemistry.chemical_compound ,Immune system ,Genes, Reporter ,Cell Line, Tumor ,Tumor Microenvironment ,Genetics ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Molecular Biology ,Oncolytic Virotherapy ,Tumor microenvironment ,Oncolytic vaccinia viru ,Animal ,Apoptosi ,Neoplasms, Experimental ,Immunotherapy ,Th1 Cells ,Xenograft Model Antitumor Assays ,Virology ,3. Good health ,Oncolytic virus ,Oncolytic Viruses ,Th1 Cell ,Urinary Bladder Neoplasms ,chemistry ,Urinary Bladder Neoplasm ,Molecular Medicine ,Genetic Vector ,Vaccinia ,Human - Abstract
Oncolytic vaccinia virus is an attractive platform for immunotherapy. Oncolysis releases tumor antigens and provides co-stimulatory danger signals. However, arming the virus can improve efficacy further. CD40 ligand (CD40L, CD154) can induce apoptosis of tumor cells and it also triggers several immune mechanisms. One of these is a T-helper type 1 (Th1) response that leads to activation of cytotoxic T-cells and reduction of immune suppression. Therefore, we constructed an oncolytic vaccinia virus expressing hCD40L (vvdd-hCD40L-tdTomato), which in addition features a cDNA expressing the tdTomato fluorochrome for detection of virus, potentially important for biosafety evaluation. We show effective expression of functional CD40L both in vitro and in vivo. In a xenograft model of bladder carcinoma sensitive to CD40L treatment, we show that growth of tumors was significantly inhibited by the oncolysis and apoptosis following both intravenous and intratumoral administration. In a CD40-negative model, CD40L expression did not add potency to vaccinia oncolysis. Tumors treated with vvdd-mCD40L-tdtomato showed enhanced efficacy in a syngenic mouse model and induced recruitment of antigen-presenting cells and lymphocytes at the tumor site. In summary, oncolytic vaccinia virus coding for CD40L mediates multiple antitumor effects including oncolysis, apoptosis and induction of Th1 type T-cell responses.
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- 2013
15. Oncolytic Adenovirus With Temozolomide Induces Autophagy and Antitumor Immune Responses in Cancer Patients
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Iulia Diaconu, Laura Ahtiainen, Timo Joensuu, Mari Hirvinen, Petri Nokisalmi, Lotta Kangasniemi, Saila K. Pesonen, Minna Oksanen, Ilkka Liikanen, Anniina Koski, Simona Bramante, Sari Pesonen, Leena Laasonen, Fang Zhao, Anna Kanerva, Otto Hemminki, Vincenzo Cerullo, Kaarina Partanen, Akseli Hemminki, Research Programs Unit, Translational Cancer Biology (TCB) Research Programme, Haartman Institute (-2014), Department of Pathology, Transplantation Laboratory, Division of Pharmaceutical Biosciences, ImmunoViroTherapy Lab, University of Helsinki, Department of Obstetrics and Gynecology, Liikanen, Ilkka, Ahtiainen, Laura, Hirvinen, Mari L., Bramante, Simona, Cerullo, Vincenzo, Nokisalmi, Petri, Hemminki, Otto, Diaconu, Iulia, Pesonen, Sari, Koski, Anniina, Kangasniemi, Lotta, Pesonen, Saila K., Oksanen, Minna, Laasonen, Leena, Partanen, Kaarina, Joensuu, Timo, Zhao, Fang, Kanerva, Anna, and Hemminki, Akseli
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Male ,GLIOBLASTOMA-MULTIFORME ,medicine.disease_cause ,Virus Replication ,T-Lymphocytes, Regulatory ,Antineoplastic Agent ,Mice ,0302 clinical medicine ,Adenosine Triphosphate ,Neoplasms ,Drug Discovery ,ADAPTIVE IMMUNITY ,HMGB1 Protein ,Child ,IN-VIVO ,Oncolytic Virotherapy ,0303 health sciences ,Cell Death ,Middle Aged ,Acquired immune system ,CONDITIONALLY REPLICATING ADENOVIRUS ,Combined Modality Therapy ,Immunohistochemistry ,3. Good health ,CONTROLLED TRIAL ,Dacarbazine ,MALIGNANT GLIOMA-CELLS ,Oncolytic Viruses ,030220 oncology & carcinogenesis ,Immunogenic cell death ,Cytokines ,Molecular Medicine ,Female ,Original Article ,REFRACTORY SOLID TUMORS ,Human ,Oncolytic adenovirus ,Adult ,Programmed cell death ,Xenograft Model Antitumor Assay ,Adolescent ,education ,Mice, Nude ,Oncolytic Viruse ,Antineoplastic Agents ,Biology ,GENE-TRANSFER ,OVARIAN-CANCER ,Adenoviridae ,03 medical and health sciences ,Young Adult ,Immune system ,Genetic ,Cell Line, Tumor ,medicine ,Autophagy ,Temozolomide ,Genetics ,Animals ,Humans ,REGULATORY T-CELLS ,Cytokine ,Cyclophosphamide ,Molecular Biology ,030304 developmental biology ,Aged ,Pharmacology ,Dose-Response Relationship, Drug ,Animal ,Drug Discovery3003 Pharmaceutical Science ,Antibodies, Neutralizing ,Xenograft Model Antitumor Assays ,Oncolytic virus ,Microscopy, Electron ,DNA, Viral ,Cancer research ,Neoplasm ,3111 Biomedicine ,Calreticulin - Abstract
Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum--a possible indicator of immune response--increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.
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- 2013
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16. Antiviral and antitumor T-cell immunity in patients treated with GM-CSF-coding oncolytic adenovirus
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Saila K. Pesonen, Ilkka Liikanen, Vincenzo Cerullo, Leena Laasonen, Lotta Kangasniemi, Petri Nokisalmi, Tuomo Alanko, Anna Kanerva, Anniina Koski, Iulia Diaconu, T. Joensuu, Minna Oksanen, Kalevi Kairemo, Raita Heiskanen, Akseli Hemminki, Sari Pesonen, Siri Tähtinen, K. Partanen, Kanerva, Anna, Nokisalmi, Petri, Diaconu, Iulia, Koski, Anniina, Cerullo, Vincenzo, Liikanen, Ilkka, Tähtinen, Siri, Oksanen, Minna, Heiskanen, Raita, Pesonen, Saila, Joensuu, Timo, Alanko, Tuomo, Partanen, Kaarina, Laasonen, Leena, Kairemo, Kalevi, Pesonen, Sari, Kangasniemi, Lotta, and Hemminki, Akseli
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Oncolytic adenovirus ,Adult ,Male ,Cancer Research ,Adolescent ,Time Factor ,medicine.medical_treatment ,Enzyme-Linked Immunosorbent Assay ,Oncolytic Viruse ,Virus ,Adenoviridae ,03 medical and health sciences ,Interferon-gamma ,Young Adult ,0302 clinical medicine ,Cancer immunotherapy ,Immunity ,Medicine ,Macrophage ,Child ,Immunologic Tolerance ,030304 developmental biology ,Aged ,Clonal Anergy ,Oncolytic Virotherapy ,0303 health sciences ,biology ,business.industry ,Tumor Necrosis Factor-alpha ,Medicine (all) ,Granulocyte-Macrophage Colony-Stimulating Factor ,Middle Aged ,Capsid Protein ,3. Good health ,Oncolytic virus ,Interleukin-10 ,Treatment Outcome ,T-Lymphocyte ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Neoplasm ,Female ,Survival Analysi ,Antibody ,business ,Human - Abstract
Purpose: Multiple injections of oncolytic adenovirus could enhance immunologic response. In the first part of this article, the focus was on immunologic aspects. Sixty patients previously naïve to oncolytic virus and who had white blood cells available were treated. Thirty-nine of 60 were assessed after a single virus administration, whereas 21 of 60 received a “serial treatment” consisting of three injections within 10 weeks. In the second part, we focused on 115 patients treated with a granulocyte macrophage colony-stimulating factor (GM–CSF)–coding capsid chimeric adenovirus, CGTG-102. Results: Following serial treatment, both increase and decrease in antitumor T cells in blood were seen more frequently, findings which are compatible with induction of T-cell immunity and trafficking of T cells to tumors, respectively. Safety was good in both groups. In 115 patients treated with CGTG-102 (Ad5/3-D24-GMCSF), median overall survival was 111 days following single and 277 days after serial treatment in nonrandomized comparison. Switching the virus capsid for avoiding neutralizing antibodies in a serial treatment featuring three different viruses did not impact safety or efficacy. A correlation between antiviral and antitumor T cells was seen (P = 0.001), suggesting that viral oncolysis can result in epitope spreading and breaking of tumor-associated immunologic tolerance. Alternatively, some patients may be more susceptible to induction of T-cell immunity and/or trafficking. Conclusions: These results provide the first human data linking antiviral immunity with antitumor immunity, implying that oncolytic viruses could have an important role in cancer immunotherapy. Clin Cancer Res; 19(10); 2734–44. ©2013 AACR.
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- 2013
17. An Oncolytic Adenovirus Enhanced for Toll-like Receptor 9 Stimulation Increases Antitumor Immune Responses and Tumor Clearance
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Matteo Ugolini, Sirkka-Liisa Holm, Valentina Romano, Iulia Diaconu, Vincenzo Cerullo, Anna Kanerva, Mari Hirvinen, Sophie Escutenaire, Anja Kipar, Akseli Hemminki, Cerullo, Vincenzo, Diaconu, Iulia, Romano, Valentina, Hirvinen, Mari, Ugolini, Matteo, Escutenaire, Sophie, Holm, Sirkka-Liisa, Kipar, Anja, Kanerva, Anna, and Hemminki, Akseli
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Oligodeoxyribonucleotide ,Lung Neoplasms ,Antineoplastic Agent ,Mice ,0302 clinical medicine ,HEK293 Cell ,Drug Discovery ,Myeloid Cells ,Receptor ,Melanoma ,Myeloid Cell ,Oncolytic Virotherapy ,0303 health sciences ,Immunogenicity ,NF-kappa B ,Combined Modality Therapy ,3. Good health ,Oncolytic Viruses ,Oligodeoxyribonucleotides ,030220 oncology & carcinogenesis ,Molecular Medicine ,Original Article ,Human ,Oncolytic adenovirus ,Xenograft Model Antitumor Assay ,Cell Survival ,Mice, Nude ,Oncolytic Viruse ,Antineoplastic Agents ,Biology ,Virus ,Adenoviridae ,03 medical and health sciences ,Immune system ,Genetic ,Cell Line, Tumor ,medicine ,Genetics ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,Pharmacology ,Animal ,Drug Discovery3003 Pharmaceutical Science ,medicine.disease ,Xenograft Model Antitumor Assays ,Oncolytic virus ,Lung Neoplasm ,Mice, Inbred C57BL ,HEK293 Cells ,Toll-Like Receptor 9 ,Cancer cell ,Immunology ,Cancer research ,CpG Islands ,CpG Island - Abstract
Oncolytic viruses represent a multifaceted tool for cancer treatment. In addition to specific killing of cancer cells (oncolysis), these agents also provide danger signals prompting the immune system to stimulate an antitumor immune response. To increase adenovirus adjuvancy, we engineered the genome of Ad5D24 by inserting 18 immunostimulatory islands (Ad5D24-CpG). The toxicity and immunogenicity profile of Ad5D24-CpG showed that the safety of the maternal virus was retained. The efficacy of the CpG-enriched virus was assessed in a xenograft model of lung cancer where a significant increase in antitumor effect was seen in comparison with controls. When the experiment was repeated in animal depleted of natural killer (NK) cells, Ad5D24-CpG lost its advantage. The same was seen when Toll-like receptor (TLR)9 was blocked systemically. In a syngeneic model of melanoma (B16-OVA), we observed a significant increase of OVA-specific T cells and a decrease of activation of myeloid-derived suppressor cells in Ad5D24-CpG–treated mice. In conclusion, we have generated the first genetically modified oncolytic adenovirus backbone able to enhance TLR9-stimulation for increased antitumor activity.
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- 2012
18. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus
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Akseli Hemminki, Angelica Loskog, Saila K. Pesonen, Simona Bramante, Suvi Parviainen, Iulia Diaconu, A. Kanerva, Aristides G. Eliopoulos, Matteo Ugolini, Sophie Escutenaire, Sari Pesonen, Mari Hirvinen, Vincenzo Cerullo, Diaconu, Iulia, Cerullo, Vincenzo, Hirvinen, Mari L. M., Escutenaire, Sophie, Ugolini, Matteo, Pesonen, Saila K., Bramante, Simona, Parviainen, Suvi, Kanerva, Anna, Loskog, Angelica S. I., Eliopoulos, Aristides G., Pesonen, Sari, and Hemminki, Akseli
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Oncolytic adenovirus ,Cancer Research ,Xenograft Model Antitumor Assay ,Genetic enhancement ,CD40 Ligand ,Melanoma, Experimental ,Mice, Nude ,chemical and pharmacologic phenomena ,Apoptosis ,Oncolytic Viruse ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Neoplasms ,Cell Line, Tumor ,Cytotoxic T cell ,Medicine ,Animals ,Humans ,CD154 ,Cytokine ,030304 developmental biology ,Oncolytic Virotherapy ,0303 health sciences ,CD40 ,biology ,business.industry ,Animal ,Apoptosi ,T-Lymphocytes, Helper-Inducer ,Virology ,Tumor site ,Xenograft Model Antitumor Assays ,3. Good health ,Mice, Inbred C57BL ,Oncolytic Viruses ,Urinary Bladder Neoplasms ,Oncology ,030220 oncology & carcinogenesis ,Urinary Bladder Neoplasm ,biology.protein ,Ovarian cancer cells ,Cytokines ,Neoplasm ,business ,Human ,T-Lymphocytes, Cytotoxic - Abstract
Oncolytic adenovirus is an attractive platform for immunotherapy because virus replication is highly immunogenic and not subject to tolerance. Although oncolysis releases tumor epitopes and provides costimulatory danger signals, arming the virus with immunostimulatory molecules can further improve efficacy. CD40 ligand (CD40L, CD154) induces apoptosis of tumor cells and triggers several immune mechanisms, including a T-helper type 1 (TH1) response, which leads to activation of cytotoxic T cells and reduction of immunosuppression. In this study, we constructed a novel oncolytic adenovirus, Ad5/3-hTERT-E1A-hCD40L, which features a chimeric Ad5/3 capsid for enhanced tumor transduction, a human telomerase reverse transcriptase (hTERT) promoter for tumor selectivity, and human CD40L for increased efficacy. Ad5/3-hTERT-E1A-hCD40L significantly inhibited tumor growth in vivo via oncolytic and apoptotic effects, and (Ad5/3-hTERT-E1A-hCD40L)–mediated oncolysis resulted in enhanced calreticulin exposure and HMGB1 and ATP release, which were suggestive of immunogenicity. In two syngeneic mouse models, murine CD40L induced recruitment and activation of antigen-presenting cells, leading to increased interleukin-12 production in splenocytes. This effect was associated with induction of the TH1 cytokines IFN-γ, RANTES, and TNF-α. Tumors treated with Ad5/3-CMV-mCD40L also displayed an enhanced presence of macrophages and cytotoxic CD8+ T cells but not B cells. Together, our findings show that adenoviruses coding for CD40L mediate multiple antitumor effects including oncolysis, apoptosis, induction of T-cell responses, and upregulation of TH1 cytokines. Cancer Res; 72(9); 2327–38. ©2012 AACR.
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- 2012
19. Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors
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Petri Nokisalmi, Satu Kauppinen, Vincenzo Cerullo, Lotta Kangasniemi, Gianpietro Dotti, Anna Kanerva, Sophie Escutenaire, Iulia Diaconu, Akseli Hemminki, Eerika Karli, Kaarina Partanen, Sari Pesonen, Elina Haavisto, Aila Karioja-Kallio, Sirkka Liisa Holm, Leena Laasonen, Timo Joensuu, Minna Oksanen, Päivi Hannuksela, Mari Raki, Kilian Guse, Pesonen, Sari, Diaconu, Iulia, Cerullo, Vincenzo, Escutenaire, Sophie, Raki, Mari, Kangasniemi, Lotta, Nokisalmi, Petri, Dotti, Gianpietro, Guse, Kilian, Laasonen, Leena, Partanen, Kaarina, Karli, Eerika, Haavisto, Elina, Oksanen, Minna, Karioja-Kallio, Aila, Hannuksela, Päivi, Holm, Sirkka-Liisa, Kauppinen, Satu, Joensuu, Timo, Kanerva, Anna, and Hemminki, Akseli
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Male ,Integrins ,Cancer Research ,viruses ,medicine.medical_treatment ,Integrin ,Virus Replication ,0302 clinical medicine ,Cancer immunotherapy ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Fatigue ,Oncolytic Virotherapy ,0303 health sciences ,ELISPOT ,Middle Aged ,Viral Load ,3. Good health ,Oncolytic Viruses ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Oligopeptide ,Female ,Genetic Vector ,Oligopeptides ,Human ,Oncolytic adenovirus ,Adult ,Fever ,Genetic Vectors ,Oncolytic Viruse ,Real-Time Polymerase Chain Reaction ,Adenoviridae ,03 medical and health sciences ,Immune system ,Cell Line, Tumor ,medicine ,Humans ,030304 developmental biology ,Tumor marker ,Aged ,Chemotherapy ,Antineoplastic Combined Chemotherapy Protocol ,business.industry ,Cancer ,Granulocyte-Macrophage Colony-Stimulating Factor ,medicine.disease ,Oncolytic virus ,Drug Resistance, Neoplasm ,Immunology ,DNA, Viral ,Cancer research ,Neoplasm ,business - Abstract
The safety of oncolytic viruses for treatment of cancer has been shown in clinical trials while antitumor efficacy has often remained modest. As expression of the coxsackie-adenovirus receptor may be variable in advanced tumors, we developed Ad5-D24-RGD, a p16/Rb pathway selective oncolytic adenovirus featuring RGD-4C modification of the fiber. This allows viral entry through alpha-v-beta integrins frequently highly expressed in advanced tumors. Advanced tumors are often immunosuppressive which results in lack of tumor eradication despite abnormal epitopes being present. Granulocyte-macrophage colony stimulating factor (GMCSF) is a potent activator of immune system with established antitumor properties. To stimulate antitumor immunity and break tumor associated immunotolerance, we constructed Ad5-RGD-D24-GMCSF, featuring GMCSF controlled by the adenoviral E3 promoter. Preliminary safety of Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of human cancer was established. Treatments with Ad5-D24-RGD (N = 9) and Ad5-RGD-D24-GMCSF (N = 7) were well tolerated. Typical side effects were grade 1-2 fatigue, fever and injection site pain. 77% (10/13) of evaluable patients showed virus in circulation for at least 2 weeks. In 3 out of 6 evaluable patients, disease previously progressing stabilized after a single treatment with Ad5-RGD-D24-GMCSF. In addition, 2/3 patients had stabilization or reduction in tumor marker levels. All patients treated with Ad5-D24-RGD showed disease progression in radiological analysis, although 3/6 had temporary reduction or stabilization of marker levels. Induction of tumor and adenovirus specific immunity was demonstrated with ELISPOT in Ad5-RGD-D24-GMCSF treated patients. RGD modified oncolytic adenoviruses with or without GMCSF seem safe for further clinical development.
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- 2012
20. Defects in innate immunity render breast cancer initiating cells permissive to oncolytic adenovirus
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Akseli Hemminki, Iulia Diaconu, Tiina Jahkola, Anna Kanerva, Cristina Mirantes, Pamela Österlund, Sophie Escutenaire, Laura Ahtiainen, Vincenzo Cerullo, Institute of Biotechnology, Research Programs Unit, Department of Surgery, Clinicum, Haartman Institute (-2014), Translational Cancer Biology (TCB) Research Programme, Division of Pharmaceutical Biosciences, Ahtiainen, Laura, Mirantes, Cristina, Jahkola, Tiina, Escutenaire, Sophie, Diaconu, Iulia, Osterlund, Pamela, Kanerva, Anna, Cerullo, Vincenzo, and Hemminki, Akseli
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Immunology/Innate Immunity ,Suppressor of Cytokine Signaling Proteins ,medicine.disease_cause ,TLR9 ,0302 clinical medicine ,IN-VIVO ,0303 health sciences ,education.field_of_study ,Multidisciplinary ,Microscopy, Confocal ,Reverse Transcriptase Polymerase Chain Reaction ,Luminescent Protein ,VESICULAR STOMATITIS-VIRUS ,TRIGGERS ,3. Good health ,Host-Pathogen Interaction ,Oncolytic Viruses ,Hyaluronan Receptors ,STAT1 Transcription Factor ,Oncology/Breast Cancer ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Interferon Type I ,Neoplastic Stem Cells ,Medicine ,Female ,Stem cell ,STEM-CELLS ,Breast Neoplasm ,Research Article ,Human ,Oncolytic adenovirus ,STAT3 Transcription Factor ,Science ,Population ,Blotting, Western ,education ,Breast Neoplasms ,Oncolytic Viruse ,Biology ,OVARIAN-CANCER ,Adenoviridae ,03 medical and health sciences ,Immune system ,Cancer stem cell ,Cell Line, Tumor ,Suppressor of Cytokine Signaling Protein ,medicine ,Immune Tolerance ,Humans ,030304 developmental biology ,IDENTIFICATION ,Cancer ,CD24 Antigen ,Cell Biology ,DNA ,medicine.disease ,EFFICACY ,Hyaluronan Receptor ,Immunity, Innate ,Toll-Like Receptor 2 ,Oncolytic virus ,Luminescent Proteins ,Toll-Like Receptor 9 ,Immunology ,Myeloid Differentiation Factor 88 ,Cancer research ,Neoplastic Stem Cell ,RESPONSES - Abstract
BackgroundCancer stem cells/initiating cells (CSC/CIC), are thought to exist as a small population in malignant tissues. They are resistant to conventional cancer treatments and possibly underlie post-treatment relapse. The CIC population can be targeted with capsid modified oncolytic adenoviruses.Methodology/principal findingsWe studied the mechanisms of innate immunity to oncolytic adenovirus Ad5/3-Delta24 in conventional treatment resistant non-CIC breast cancer cells, breast cancer CD44(+)/CD24(-/low) CIC population and normal breast tissue CD44(+)/CD24(-/low) stem cells. We compared virus recognition by pattern recognition receptors for adenovirus, Toll-like receptors (TLR) 2 and 9 and virus induced type I interferon (IFN) response regulation in these cell types. We show TLR mediated virus recognition in these non-immune cell types. Normal tissue stem cells have intact type I IFN signaling. Furthermore, TLR9 and TLR2 reside constantly in recognition sites, implying constant activation. In contrast, breast cancer CD44(+)/CD24(-/low) CIC have dysregulated innate immune responses featuring dysfunctional virus recognition caused by impaired trafficking of TLR9 and cofactor MyD88 and the absence of TLR2, having a deleterious impact on TLR pattern recognition receptor signaling. Furthermore, the CIC have increased inhibitory signaling via the suppressor of cytokine signaling/Tyro3/Axl/Mer receptor tyrosine kinase (SOCS/TAM) pathway. These defects in contribute to dysfunctional induction of type I IFN response in CIC and therefore permissivity to oncolytic adenovirus.Conclusions/significanceCICs may underlie the incurable nature of relapsed or metastatic cancers and are therefore an important target regarding diagnostic and prognostic aspects as well as treatment of the disease. This study addresses the mechanisms of innate infection immunity in stem cells deepening the understanding of stem cell biology and may benefit not only virotherapy but also immunotherapy in general.
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- 2010
21. Exploiting pre-existing immunity to enhance oncolytic cancer immunotherapy
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Vincenzo Cerullo, Karita Peltonen, Siri Tähtinen, Marta Medeot, Tuuli Ranki, Manlio Fusciello, Maria Tagliamonte, Erkko Ylösmäki, Christianne Groeneveldt, Firas Hamdan, Jacopo Chiaro, Luigi Buonaguro, Cristian Capasso, Leena Ylösmäki, Netta Laustio, Sara Feola, Beatriz Martins, Tahtinen, S., Feola, S., Capasso, C., Laustio, N., Groeneveldt, C., Ylosmaki, E. O., Ylosmaki, L., Martins, B., Fusciello, M., Medeot, M., Tagliamonte, M., Chiaro, J., Hamdan, F., Peltonen, K., Ranki, T., Buonaguro, L., and Cerullo, V.
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0301 basic medicine ,Oncolytic adenovirus ,CD4-Positive T-Lymphocytes ,Cancer Research ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Melanoma, Experimental ,Oncolytic Viruse ,Cancer Vaccines ,Adenoviridae ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Antineoplastic Agents, Immunological ,Cancer immunotherapy ,Antigen ,Immunity ,Antigens, Neoplasm ,Cell Line, Tumor ,Medicine ,Animals ,Humans ,Vaccines, Combined ,Diphtheria-Tetanus-Pertussis Vaccine ,business.industry ,Animal ,Histocompatibility Antigens Class I ,Histocompatibility Antigens Class II ,Dendritic cell ,3. Good health ,Oncolytic virus ,Oncolytic Viruses ,Poliovirus Vaccine, Inactivated ,030104 developmental biology ,Oncology ,Tetanus vaccine ,CD4-Positive T-Lymphocyte ,030220 oncology & carcinogenesis ,Cancer research ,Female ,Immunotherapy ,business ,Immunologic Memory ,medicine.drug ,Cancer Vaccine ,Human ,T-Lymphocytes, Cytotoxic - Abstract
Because of the high coverage of international vaccination programs, most people worldwide have been vaccinated against common pathogens, leading to acquired pathogen-specific immunity with a robust memory T-cell repertoire. Although CD8+ antitumor cytotoxic T lymphocytes (CTL) are the preferred effectors of cancer immunotherapy, CD4+ T-cell help is also required for an optimal antitumor immune response to occur. Hence, we investigated whether the pathogen-related CD4+ T-cell memory populations could be reengaged to support the CTLs, converting a weak primary antitumor immune response into a stronger secondary one. To this end, we used our PeptiCRAd technology that consists of an oncolytic adenovirus coated with MHC-I–restricted tumor-specific peptides and developed it further by introducing pathogen-specific MHC-II–restricted peptides. Mice preimmunized with tetanus vaccine were challenged with B16.OVA tumors and treated with the newly developed hybrid TT-OVA-PeptiCRAd containing both tetanus toxoid- and tumor-specific peptides. Treatment with the hybrid PeptiCRAd significantly enhanced antitumor efficacy and induced TT-specific, CD40 ligand-expressing CD4+ T helper cells and maturation of antigen-presenting cells. Importantly, this approach could be extended to naturally occurring tumor peptides (both tumor-associated antigens and neoantigens), as well as to other pathogens beyond tetanus, highlighting the usefulness of this technique to take full advantage of CD4+ memory T-cell repertoires when designing immunotherapeutic treatment regimens. Finally, the antitumor effect was even more prominent when combined with the immune checkpoint inhibitor anti–PD-1, strengthening the rationale behind combination therapy with oncolytic viruses. Significance: These findings establish a novel technology that enhances oncolytic cancer immunotherapy by capitalizing on pre-acquired immunity to pathogens to convert a weak antitumor immune response into a much stronger one.
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