Journal Articles

Oncolytic viruses

Therapies based on tumor-targeting cytolytic viruses, including oncolytic viruses armed with immunomodulatory transgenes

Chikungunya-vesicular stomatitis chimeric virus targets and eliminates brain tumors

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Vesicular stomatitis virus (VSV) shows potential for targeting and killing cancer cells, but can be dangerous in the brain due to its neurotropic glycoprotein. Here we test a chimeric virus in which the VSV glycoprotein is replaced with the Chikungunya polyprotein E3-E2-6K-E1 (VSVDeltaG-CHIKV). Control mice with brain tumors survived a mean of 40 days after tumor implant. VSVDeltaG-CHIKV selectively infected and eliminated the tumor, and extended survival substantially in all tumor-bearing mice to over 100 days. VSVDeltaG-CHIKV also targeted intracranial primary patient derived melanoma xenografts. Virus injected into one melanoma spread to other melanomas within the same brain with little detectable infection of normal cells. Intravenous VSVDeltaG-CHIKV infected tumor cells but not normal tissue. In immunocompetent mice, VSVDeltaG-CHIKV selectively infected mouse melanoma cells within the brain. These data suggest VSVDeltaG-CHIKV can target and destroy brain tumors in multiple animal models without the neurotropism associated with the wild type VSV glycoprotein.

Author Info: (1) Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, United States. (2) Department of Neurosurgery, Yale University School

Author Info: (1) Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, United States. (2) Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, United States. (3) Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, United States. Electronic address: anthony.vandenpol@yale.edu.

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Zika virus as an oncolytic treatment of human neuroblastoma cells requires CD24

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Neuroblastoma is the second most common childhood tumor. Survival is poor even with intensive therapy. In a search for therapies to neuroblastoma, we assessed the oncolytic potential of Zika virus. Zika virus is an emerging mosquito-borne pathogen unique among flaviviruses because of its association with congenital defects. Recent studies have shown that neuronal progenitor cells are likely the human target of Zika virus. Neuroblastoma has been shown to be responsive to infection. In this study, we show that neuroblastoma cells are widely permissive to Zika infection, revealing extensive cytopathic effects (CPE) and producing high titers of virus. However, a single cell line appeared poorly responsive to infection, producing undetectable levels of non-structural protein 1 (NS1), limited CPE, and low virus titers. A comparison of these poorly permissive cells to highly permissive neuroblastoma cells revealed a dramatic loss in the expression of the cell surface glycoprotein CD24 in poorly permissive cells. Complementation of CD24 expression in these cells led to the production of detectable levels of NS1 expression after infection with Zika, as well as dramatic increases in viral titers and CPE. Complementary studies using the Zika virus index strain and a north African isolate confirmed these phenotypes. These results suggest a possible role for CD24 in host cell specificity by Zika virus and offer a potential therapeutic target for its treatment. In addition, Zika viral therapy can serve as an adjunctive treatment for neuroblastoma by targeting tumor cells that can lead to recurrent disease and treatment failure.

Author Info: (1) Department of Biomedical Research, Nemours Children's Hospital, Orlando, Florida, United States of America. (2) Burnett School of Biological Sciences, University of Central Florida College

Author Info: (1) Department of Biomedical Research, Nemours Children's Hospital, Orlando, Florida, United States of America. (2) Burnett School of Biological Sciences, University of Central Florida College of Medicine, Orlando, Florida, United States of America. (3) Department of Biomedical Research, Nemours Children's Hospital, Orlando, Florida, United States of America. (4) Department of Biomedical Research, Nemours Children's Hospital, Orlando, Florida, United States of America. (5) Burnett School of Biological Sciences, University of Central Florida College of Medicine, Orlando, Florida, United States of America. (6) Burnett School of Biological Sciences, University of Central Florida College of Medicine, Orlando, Florida, United States of America. (7) Department of Biomedical Research, Nemours Children's Hospital, Orlando, Florida, United States of America. Burnett School of Biological Sciences, University of Central Florida College of Medicine, Orlando, Florida, United States of America. (8) Department of Biomedical Research, Nemours Children's Hospital, Orlando, Florida, United States of America. Burnett School of Biological Sciences, University of Central Florida College of Medicine, Orlando, Florida, United States of America.

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Recombinant oncolytic Newcastle disease virus displays antitumor activities in anaplastic thyroid cancer cells

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BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors for which no effective therapies are currently available. Oncolytic Newcastle disease virus (NDV) has shown the potential to induce oncolytic cell death in a variety of cancer cells of diverse origins. However, whether oncolytic NDV displays antitumor effects in ATC remains to be investigated. We have previously shown that the oncolytic NDV strain FMW (NDV/FMW) induces oncolytic cell death in several cancer types. In the present study, we investigated the oncolytic effects of NDV/FMW in ATC. METHODS: In this study, a recombinant NDV expressing green fluorescent protein (GFP) was generated using an NDV reverse genetics system. The resulting virus was named after rFMW/GFP and the GFP expression in infected cells was demonstrated by direct fluorescence and immunoblotting. Viral replication was evaluated by end-point dilution assay in DF-1 cell lines. Oncolytic effects were examined by biochemical and morphological experiments in cultural ATC cells and in mouse models. RESULTS: rFMW/GFP replicated robustly in ATC cells as did its parent virus (NDV/FMW) while the expression of GFP protein was detected in lungs and spleen of mice intravenously injected with rFMW/GFP. We further showed that rFMW/GFP infection substantially increased early and late apoptosis in the ATC cell lines, THJ-16 T and THJ-29 T and increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage in ATC cells as assessed by immunoblotting. In addition, rFMW/GFP induced lyses of spheroids derived from ATC cells in three-dimensional (3D) cultures. We further demonstrated that rFMW/GFP infection resulted in the activation of p38 MAPK signaling, but not Erk1/2 or JNK, in THJ-16 T and THJ-29 T cells. Notably, inhibition of p38 MAPK activity by SB203580 decreased rFMW/GFP-induced cleavage of caspase-3 and PARP in THJ-16 T and THJ-29 T cells. Finally, both rFMW/GFP and its parent virus inhibited tumor growth in mice bearing THJ-16 T derived tumors. CONCLUSION: Taken together, these data indicate that both the recombinant reporter virus rFMW/GFP and its parent virus NDV/FMW, display oncolytic activities in ATC cells in vitro and in vivo and suggest that oncolytic NDV may have potential as a novel therapeutic strategy for ATC.

Author Info: (1) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (2) Department of Avian Infectious

Author Info: (1) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (2) Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 518 Ziyue Road, Shanghai, 200241, China. (3) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (4) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (5) Laboratory Center, The Third People's Hospital of Huizhou, Affiliated Hospital Guangzhou Medical University, Huizhou, 516002, China. (6) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (7) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (8) Department of Dermatology of First Affiliated Hospital, Dalian Medical University, No. 222 Zhongshan Road, Dalian, 116021, China. (9) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (10) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (11) Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences St. James's Hospital and Trinity College Dublin, Dublin, Ireland. (12) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. (13) Central laboratory, Liaoning Cancer Hospital and Institute, Cancer Hospital of China Medical University, 44 Xiaoheyan Road, Shenyang, 110042, China. zhang.lth@163.com. (14) Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 518 Ziyue Road, Shanghai, 200241, China. shoveldeen@shvri.ac.cn. (15) Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Room 415, 9 Lvshun Road South, Dalian, 116044, China. ssmeng@dmu.edu.cn.

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Characterization of a replicating expanded tropism oncolytic reovirus carrying the adenovirus E4orf4 gene

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While the mammalian orthoreovirus type 3 dearing (reovirus T3D) infects many different tumour cells, various cell lines resist the induction of reovirus-mediated cell death. In an effort to increase the oncolytic potency, we introduced transgenes into the S1 segment of reovirus T3D. The adenovirus E4orf4 gene was selected as transgene since the encoded E4orf4 protein induces cell death in transformed cells. The induction of cell death by E4orf4 depends in part on its binding to phosphatase 2A (PP2A). In addition to the S1-E4orf4 reovirus, two other reoviruses were employed in our studies. The reovirus rS1-RFA encodes an E4orf4 double-mutant protein that cannot interact with PP2A and the rS1-iLOV virus encoding the fluorescent marker iLOV as a reporter. The replacement of the codons for the junction adhesion molecule-A (JAM-A) binding head domain of the truncated spike protein blocks the entry of these recombinant viruses via the reovirus receptor JAM-A. Instead these viruses rely on internalization via binding to sialic acids on the cell surface. This expands their tropism and allows infection of JAM-A-deficient tumour cells. Here we not only demonstrate the feasibility of this approach but also established that the cytolytic activity of these recombinant viruses is largely transgene independent.

Author Info: (1) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (2) Department of Cell and Chemical Biology, Leiden University Medical Center

Author Info: (1) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (2) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (3) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (4) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. (5) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands. d.j.m.van_den_wollenberg@lumc.nl.

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Personalized Cancer Vaccine Platform for Clinically Relevant Oncolytic Enveloped Viruses

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The approval of the first oncolytic virus for the treatment of metastatic melanoma and the compiling evidence that the use of oncolytic viruses can enhance cancer immunotherapies targeted against various immune checkpoint proteins has attracted great interest in the field of cancer virotherapy. We have developed a novel platform for clinically relevant enveloped viruses that can direct the virus-induced immune response against tumor antigens. By physically attaching tumor-specific peptides onto the viral envelope of vaccinia virus and herpes simplex virus 1 (HSV-1), we were able to induce a strong T cell-specific immune response toward these tumor antigens. These therapeutic peptides could be attached onto the viral envelope by using a cell-penetrating peptide sequence derived from human immunodeficiency virus Tat N-terminally fused to the tumor-specific peptides or, alternatively, therapeutic peptides could be conjugated with cholesterol for the attachment of the peptides onto the viral envelope. We used two mouse models of melanoma termed B16.OVA and B16-F10 for testing the efficacy of OVA SIINFEKL-peptide-coated viruses and gp100-Trp2-peptide-coated viruses, respectively, and show that by coating the viral envelope with therapeutic peptides, the anti-tumor immunity and the number of tumor-specific CD8(+) T cells in the tumor microenvironment can be significantly enhanced.

Author Info: (1) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (2) Laboratory of Immunovirotherapy, Drug Research Program

Author Info: (1) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (2) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (3) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (4) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (5) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (6) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (7) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (8) Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (9) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (10) Department of Virology, University of Turku, Kiinamyllynkatu 13, 20520, Turku, Finland. (11) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (12) Department of Virology, University of Turku, Kiinamyllynkatu 13, 20520, Turku, Finland. (13) Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. (14) Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00790 Helsinki, Finland. Electronic address: vincenzo.cerullo@helsinki.fi.

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Preclinical Development of Oncolytic Immunovirotherapy for Treatment of HPV(POS) Cancers

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Immunotherapy for HPV(POS) malignancies is attractive because well-defined, viral, non-self tumor antigens exist as targets. Several approaches to vaccinate therapeutically against HPV E6 and E7 antigens have been adopted, including viral platforms such as VSV. A major advantage of VSV expressing these antigens is that VSV also acts as an oncolytic virus, leading to direct tumor cell killing and induction of effective anti-E6 and anti-E7 T cell responses. We have also shown that addition of immune adjuvant genes, such as IFNbeta, further enhances safety and/or efficacy of VSV-based oncolytic immunovirotherapies. However, multiple designs of the viral vector are possible-with respect to levels of immunogen expression and method of virus attenuation-and optimal designs have not previously been tested head-to-head. Here, we tested three different VSV engineered to express a non-oncogenic HPV16 E7/6 fusion protein for their immunotherapeutic and oncolytic properties. We assessed their profiles of efficacy and toxicity against HPV(POS) and HPV(NEG) murine tumor models and determined the optimal route of administration. Our data show that VSV is an excellent platform for the oncolytic immunovirotherapy of tumors expressing HPV target antigens, combining a balance of efficacy and safety suitable for evaluation in a first-in-human clinical trial.

Author Info: (1) Imanis Life Sciences, Rochester, MN 55902, USA. (2) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (3) Imanis Life Sciences, Rochester, MN 55902, USA

Author Info: (1) Imanis Life Sciences, Rochester, MN 55902, USA. (2) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (3) Imanis Life Sciences, Rochester, MN 55902, USA. (4) Imanis Life Sciences, Rochester, MN 55902, USA. (5) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (6) Imanis Life Sciences, Rochester, MN 55902, USA. (7) Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, MN 55905, USA. (8) Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, MN 55905, USA. (9) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (10) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (11) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (12) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (13) Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, MN 55905, USA. Vyriad, Inc., Rochester, MN 55902, USA. Deparment of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (14) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (15) Profectus Biosciences, Inc., Pearl River, NY 10965, USA. (16) Vyriad, Inc., Rochester, MN 55902, USA. Deparment of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA. (17) Vyriad, Inc., Rochester, MN 55902, USA.

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Remission of spontaneous canine tumors after systemic cellular viroimmunotherapy

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Dogs with spontaneous tumors treated in veterinary hospitals offer an excellent opportunity for studying immunotherapies, including oncolytic viruses. Oncolytic viruses have advanced into the clinic as an intratumorally administered therapeutic; however, intravenous delivery has been hindered by neutralization in the blood. To circumvent this hurdle, mesenchymal stem cells have been used as a "Trojan horse". Here we present the treatment of 27 canine cancer patients with canine mesenchymal stem cells infected with ICOCAV17, a canine oncolytic adenovirus. No significant adverse effects were found. The response rate was 74%, with 14.8% showing complete responses, including total remissions of lung metastasis. We detected virus infection, stromal degeneration, and immune cell infiltration in tumor biopsies after four weeks of treatment. The increased presence of anti-adenoviral antibodies in the peripheral blood of treated dogs did not appear to prevent the clinical benefit of this therapy. These data indicate that oncolytic viruses loaded in mesenchymal stem cells represent an effective cancer immunotherapy.

Author Info: (1) Unidad de Biotecnologia Celular, Instituto de Salud Carlos III. (2) Unidad de Biotecnologia Celular, Instituto de Salud Carlos III. (3) Veterinary Hospital, Alfonso X

Author Info: (1) Unidad de Biotecnologia Celular, Instituto de Salud Carlos III. (2) Unidad de Biotecnologia Celular, Instituto de Salud Carlos III. (3) Veterinary Hospital, Alfonso X el Sabio University. (4) Translational Research Laboratory, IDIBELL-Institut Catala d'Oncologia. (5) Unidad de Biotecnologia Celular, Instituto de Salud Carlos III. (6) Unidad de Biotecnologia Celular, Instituto de Salud Carlos III. (7) Veterinary Hospital, Alfonso X el Sabio University. (8) Veterinary Hospital, Alfonso X el Sabio University. (9) Servicio de Oncohematologia,, Hospital Universitario Nino Jesus. (10) Oncobell and ProCure Programs, IDIBELL-Institut Catala d'Oncologia. (11) Veterinary Hospital, Alfonso X el Sabio University. (12) Unidad de Biotecnologia Celular, Instituto de Salud Carlos III jgcastro@isciii.es.

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Oncograms Visualize Factors Influencing Long-Term Survival of Cancer Patients Treated with Adenoviral Oncolytic Immunotherapy

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The first US Food and Drug Administration (FDA)- and EMA-approved oncolytic virus has been available since 2015. However, there are no markers available that would predict benefit for the individual patient. During 2007-2012, we treated 290 patients with advanced chemotherapy-refractory cancers, using 10 different oncolytic adenoviruses. Treatments were given in a Finnish Medicines Agency (FIMEA)-regulated individualized patient treatment program (the Advanced Therapy Access Program [ATAP]), which required long-term follow-up of patients, which is presented here. Focusing on the longest surviving patients, some key clinical and biological features are presented as "oncograms." Some key attributes that could be captured in the oncogram are suggested to predict treatment response and survival after oncolytic adenovirus treatment. The oncogram includes immunological laboratory parameters assessed in peripheral blood (leukocytes, neutrophil-to-lymphocyte ratio, interleukin-8 [IL-8], HMGB1, anti-viral neutralizing antibody status), features of the patient (gender, performance status), tumor features (histological tumor type, tumor load, region of metastases), and oncolytic virus-specific features (arming of the virus). The retrospective approach used here facilitates verification in a prospective controlled trial setting. To our knowledge, the oncogram is the first holistic attempt to identify the patients most likely to benefit from adenoviral oncolytic virotherapy.

Author Info: (1) Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Department of Urology, Helsinki University Hospital, Helsinki, Finland. (2)

Author Info: (1) Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Department of Urology, Helsinki University Hospital, Helsinki, Finland. (2) Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. (3) Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. (4) Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. (5) Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Department of Neurosurgery, Helsinki University Hospital, Helsinki, Finland. (6) Docrates Hospital, Helsinki, Finland. (7) Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland. (8) Cancer Gene Therapy Group, Department of Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland. Docrates Hospital, Helsinki, Finland. TILT Biotherapeutics Ltd., Helsinki, Finland. Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.

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Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus

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As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-mum precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer.

Author Info: (1) Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK

Author Info: (1) Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK. (2) Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK. (3) Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK. (4) Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK. (5) Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK. (6) The Institute of Cancer Research, London SM2 5PT, UK. (7) Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK. (8) Viralytics Limited, Suite 305, Level 3, 66 Hunter Street, Sydney, NSW 2000, Australia. (9) Viralytics Limited, Suite 305, Level 3, 66 Hunter Street, Sydney, NSW 2000, Australia. (10) Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK. (11) The Institute of Cancer Research, London SM2 5PT, UK. (12) Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55902, USA. (13) The Institute of Cancer Research, London SM2 5PT, UK. (14) Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, Leggett Building, Daphne Jackson Road, University of Surrey, Guildford GU2 7WG, UK.

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Systemically Administered Sindbis Virus in Combination with Immune Checkpoint Blockade Induces Curative Anti-tumor Immunity

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Oncolytic viruses represent a promising form of cancer immunotherapy. We investigated the potential of Sindbis virus (SV) for the treatment of solid tumors expressing the human cancer testis antigen NYESO-1. NYESO-1 is an immunogenic antigen frequently expressed in numerous cancers, such as ovarian cancer. We show that SV expressing the tumor-associated antigen NYESO-1 (SV-NYESO1) acts as an immunostimulatory agent, inducing systemic and rapid lymphocyte activation, leading to a pro-inflammatory environment. SV-NYESO1 treatment combined with anti-programmed death 1 (anti-PD-1) markedly augmented the anti-tumor immunity in mice over the course of treatment, resulting in an avid systemic and intratumoral immune response. This response involved reduced presence of granulocytic myeloid-derived suppressor cells in tumors and an increase in the activation of splenic and tumor-infiltrating T cells. Combined therapy also induced enhanced cytotoxic activity of T cells against NYESO-1-expressing tumors. These results were in line with an observed inverse correlation between T cell activation and tumor growth. Finally, we show that combined therapy resulted in complete clearance of NYESO-1-expressing tumors in vivo and led to long-term protection against recurrences. These findings provide a rationale for clinical studies of SV-NYESO1 combined with immune checkpoint blockade anti-PD-1 to be used in the treatment of NYESO-1-expressing tumors.

Author Info: (1) Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. (2) Department of Pathology, NYU School of Medicine, New York, NY 10016

Author Info: (1) Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. (2) Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. (3) Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. (4) Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. (5) Department of Pathology, NYU School of Medicine, New York, NY 10016, USA. (6) Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.

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