Journal Articles

Oncolytic viruses

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

Immune Consequences of in vitro Infection of Human Peripheral Blood Leukocytes with Vesicular Stomatitis Virus

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BACKGROUND: Oncolytic vesicular stomatitis virus (VSV) can be delivered intravenously to target primary and metastatic lesions, but the interaction between human peripheral blood leukocytes (PBLs) and VSV remains poorly understood. Our study aimed to assess the overall immunological consequences of ex vivo infection of PBLs with VSV. METHODS: Phenotypic analysis of lymphocyte subsets and apoptosis were evaluated with flow cytometry. Caspase 3/7 activity was detected by luminescence assay. Virus release was evaluated in a murine cell line (L929). Gene expression and cytokine/chemokine secretion were assessed by real-time PCR and multiplex assay, respectively. RESULTS: Ex vivo infection of PBLs with VSV elicited upregulated expression of RIG-I, MDA-5, tetherin, IFITM3, and MxA. VSV infection triggered rapid differentiation of blood monocytes into immature dendritic cells as well as their apoptosis, which depended on caspase 3/7 activation. Monocyte differentiation required infectious VSV, but loss of CD14+ cells was also associated with the presence of a cytokine/chemokine milieu produced in response to VSV infection. CONCLUSIONS: Systemic delivery is a major goal in the field of oncolytic viruses. Our results shed further light on immune mechanisms in response to VSV infection and the underlying VSV-PBL interactions bringing hope for improved cancer immunotherapies, particularly those based on intravenous delivery of oncolytic VSV.

Author Info: (1) Laboratory of Virology, Institute of Immunology and Experimental Therapy (IIET), Polish Academy of Sciences, Wroclaw, Poland. (2) (3) (4) (5) (6) (7)

Author Info: (1) Laboratory of Virology, Institute of Immunology and Experimental Therapy (IIET), Polish Academy of Sciences, Wroclaw, Poland. (2) (3) (4) (5) (6) (7)

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Transcriptional retargeting of herpes simplex virus for cell-specific replication to control cancer

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INTRODUCTION: Oncolytic virotherapy has emerged as a novel frontier in the treatment of cancer. Among the viruses that entered clinical trials are the oncolytic herpes simplex virus-1 (HSV-1). Current oncolytic HSV-1 approved for clinical practice, and those in clinical trials are attenuated viruses, often deleted in the neurovirulence gene gamma134.5, and in additional genes, which may result in a much more attenuated virus with reduced replication efficiency. Therefore, the transcriptional retargeting strategy by modifying the regulator elements flanking essential viral genes to achieve tumor-specific replication while maintaining as much of the viral genome has been representing alternative promising oncolytic virotherapy modality. MATERIALS AND METHODS: In this communication, we aimed to review extensive studies on transcriptional retargeting strategy with HSV-1 genome engineered on immediate-early ICP4 gene, late gamma134.5 gene or early ICP6 gene as well as multiple-regulated oncolytic HSV1 through combining transcriptional retargeting and translational control. Design modality based on differential cellular background, advantage, and potential clinic limitation of the innovative oncolytic HSV-1 was described, and prospective and challenge of transcriptional retargeting strategy were collectively summarized. CONCLUSION: Transcriptional retargeting strategy holds great promise in retaining tumor specificity as well as full replication capacity of oncolytic virus in the target cell as urgently required by clinical trials. Future efforts should be aimed toward the development of multiple-component targeted oncolytic virus such as combing the transcriptional retargeting strategy and genetically attenuated modulation or post-transcriptional control that will be the most effective at generating truly tumor selective vectors.

Author Info: (1) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology

Author Info: (1) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. (2) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. (3) Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA. (4) Viri Biotechnology Company Limited, No. 8 Guohuai Street, Zhengzhou, Henan, 450052, China. (5) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. diwen163@163.com. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. diwen163@163.com. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, 10032, USA. diwen163@163.com. Viri Biotechnology Company Limited, No. 8 Guohuai Street, Zhengzhou, Henan, 450052, China. diwen163@163.com. (6) Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200126, China. ningning1723@126.com. Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200126, China. ningning1723@126.com.

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Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade

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Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation would up-regulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous administration will not deliver virus to this site. We show, in a window-of-opportunity clinical study, that intravenous infusion of oncolytic human Orthoreovirus (referred to herein as reovirus) leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus up-regulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.

Author Info: (1) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS

Author Info: (1) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. a.samson@leeds.ac.uk alan.melcher@icr.ac.uk s.c.short@leeds.ac.uk. (2) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (3) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (4) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (5) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (6) Ohio State University, Comprehensive Cancer Centre, Columbus, OH 43210, USA. (7) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (8) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (9) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (10) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (11) Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. (12) Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. (13) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (14) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (15) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (16) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (17) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (18) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (19) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (20) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (21) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (22) Oncolytics Biotech, Calgary, Alberta T2N 1X7, Canada. (23) Leeds Teaching Hospitals National Health Service Trust, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (24) Leeds Institute of Clinical Trials Research, Faculty of Medicine and Health, University of Leeds, Leeds, West Yorkshire LS2 9JT, UK. (25) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (26) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (27) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (28) University College London, London WC1 6BT, UK. (29) University College London, London WC1 6BT, UK. (30) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (31) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (32) University of Surrey, Guildford GU2 7XH, UK. (33) Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK. (34) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (35) Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. (36) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (37) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. (38) Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, St James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK. a.samson@leeds.ac.uk alan.melcher@icr.ac.uk s.c.short@leeds.ac.uk. (39) Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK. a.samson@leeds.ac.uk alan.melcher@icr.ac.uk s.c.short@leeds.ac.uk.

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Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy

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Triple-negative breast cancer (TNBC) is an aggressive disease for which treatment options are limited and associated with severe toxicities. Immunotherapeutic approaches like immune checkpoint inhibitors (ICIs) are a potential strategy, but clinical trials have demonstrated limited success in this patient cohort. Clinical studies using ICIs have revealed that patients with preexisting anticancer immunity are the most responsive. Given that oncolytic viruses (OVs) induce antitumor immunity, we investigated their use as an ICI-sensitizing approach. Using a therapeutic model that mimics the course of treatment for women with newly diagnosed TNBC, we demonstrate that early OV treatment coupled with surgical resection provides long-term benefits. OV therapy sensitizes otherwise refractory TNBC to immune checkpoint blockade, preventing relapse in most of the treated animals. We suggest that OV therapy in combination with immune checkpoint blockade warrants testing as a neoadjuvant treatment option in the window of opportunity between TNBC diagnosis and surgical resection.

Author Info: (1) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. mbourgeois@ohri.ca jbell@ohri.ca. Department of Biochemistry, Microbiology and Immunology, University of Ottawa

Author Info: (1) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. mbourgeois@ohri.ca jbell@ohri.ca. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. (2) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. (3) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. (4) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. (5) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. (6) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. (7) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. (8) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. (9) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. (10) Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton L8S 4K1, Canada. (11) Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. Children's Hospital of Eastern Ontario Research Institute, Ottawa K1H 8L1, Canada. (12) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. (13) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada. (14) Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa K1H 8L6, Canada. mbourgeois@ohri.ca jbell@ohri.ca. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H 8M5, Canada.

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Overcoming resistance to anti-PD immunotherapy in a syngeneic mouse lung cancer model using locoregional virotherapy

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Anti-PD-1 and anti-PD-L1 immunotherapy has provided a new therapeutic opportunity for treatment of advanced-stage non-small cell lung cancer (NSCLC). However, overall objective response rates are approximately 15%-25% in all NSCLC patients who receive anti-PD therapy. Therefore, strategies to overcome primary resistance to anti-PD immunotherapy are urgently needed. We hypothesized that the barrier to the success of anti-PD therapy in most NSCLC patients can be overcome by stimulating the lymphocyte infiltration at cancer sites through locoregional virotherapy. To this end, in this study, we determined combination effects of anti-PD immunotherapy and oncolytic adenoviral vector-mediated tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) gene therapy (Ad/E1-TRAIL) or adenoviral-mediated TP53 (Ad/CMV-TP53) gene therapy in syngeneic mice bearing subcutaneous tumors derived from M109 lung cancer cells. Both anti-PD-1 and anti-PD-L1 antibodies failed to elicit obvious therapeutic effects in the M109 tumors. Intratumoral administration of Ad/E1-TRAIL or Ad/CMV-TP53 alone suppressed tumor growth in animals preexposed to an adenovector and bearing subcutaneous tumors derived from M109 cells. However, combining either anti-PD-1 or anti-PD-L1 antibody with these two adenoviral vectors elicited the strongest anticancer activity in mice with existing immunity to adenoviral vectors. Dramatically enhanced intratumoral immune response was detected in this group of combination therapy based on infiltrations of CD4+ and CD8+ lymphocytes and macrophages in tumors. Our results demonstrate that resistance to anti-PD-1 immunotherapy in syngeneic mouse lung cancer can be overcome by locoregional virotherapy.

Author Info: (1) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Medical Oncology, Chinese PLA General

Author Info: (1) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China. (2) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

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A Recombinant Antibody-Expressing Influenza Virus Delays Tumor Growth in a Mouse Model

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Influenza A virus (IAV) has shown promise as an oncolytic agent. To improve IAV as an oncolytic virus, we sought to design a transgenic virus expressing an immune checkpoint-inhibiting antibody during the viral life cycle. To test whether it was possible to express an antibody during infection, an influenza virus was constructed encoding the heavy chain of an antibody on the PB1 segment and the light chain of an antibody on the PA segment. This antibody-expressing IAV grows to high titers, and the antibodies secreted from infected cells exhibit comparable functionality with hybridoma-produced antibodies. To enhance the anti-cancer activity of IAV, an influenza virus was engineered to express a single-chain antibody antagonizing the immune checkpoint CTLA4 (IAV-CTLA4). In mice implanted with the aggressive B16-F10 melanoma, intratumoral injection with IAV-CTLA4 delayed the growth of treated tumors, mediated an abscopal effect, and increased overall survival.

Author Info: (1) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (2) Department of Microbiology, Icahn School of Medicine at

Author Info: (1) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (2) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (3) Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: peter.palese@mssm.edu.

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Fighting Cancer with Viruses: Oncolytic Virus Therapy in China

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Oncolytic virus has the special property with selective infection of tumor cells, leading to oncolysis of cancer cells and minimal toxicity to normal tissues, which is administrated in cancer therapy called oncolytic virotherapy. As a biological agent, oncolytic virus could induce tumor cell lysis, local immunological reaction, and enhance systemic anti-tumor immunity. These immune stimulatory properties of oncolytic virus will provide enormous benefits to override cancer. Nowadays, a great variety of oncolytic viruses including genetically engineered and natural viruses have shown promise in preclinical models and clinical studies. Oncolytic virus has been investigated for cancer treatment in China since the 1980s. In 2005, the China Food and Drug Administration approved its first oncolytic virus drug, Oncorine (H101) for treatment of advanced head and neck cancer. To explore new treatment strategy, more than two hundred recombinant or natural oncolytic viruses are investigated in-depth in China, and more than two hundred and fifty oncolytic virotherapy-related reports from Chinese oncolytic virus community were published in the past five years. In these studies, a number of exogenous genes and combination therapeutic strategies were investigated to enhance the treatment effects of oncolytic virus. Up to now, five clinical trials covering four oncolytic virus agents (Oncorine, OrienX010, KH901, and H103) are ongoing, and more and more oncolytic virus agents are waiting for approval of clinical trials in China. Based on these works, we believe that the combination therapy, especially with tumor immunotherapy coupled with effective system administration strategy, would promote the development of oncolytic virotherapy. Here, we focus on the studies that carried out in China to show the past, present, and future of oncolytic virotherapy in China.

Author Info: (1) Fourth Military Medical University, 12644, Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Xi'an, Shaanxi

Author Info: (1) Fourth Military Medical University, 12644, Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Xi'an, Shaanxi, China ; weiding@189.cn. (2) Fourth Military Medical University, 12644, Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Xi'an, Shaanxi, China ; lightxj@hotmail.com. (3) Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Institute of Biochemistry and Cell Biology, Shanghai, China ; xyliu@sibs.ac.cn. (4) Fourth Military Medical University, Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Xi'an, Shaanxi, China ; znchen@fmmu.edu.cn. (5) Fourth Military Medical University, Department of Cell Biology, National Translational Science Center for Molecular Medicine, State Key Laboratory of Cancer Biology, Xi'an, China ; hjbian@fmmu.edu.cn.

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Generation and Functional In Vitro Analysis of Semliki Forest Virus Vectors Encoding TNF-alpha and IFN-gamma

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Cytokine gene delivery by viral vectors is a promising novel strategy for cancer immunotherapy. Semliki Forest virus (SFV) has many advantages as a delivery vector, including the ability to (i) induce p53-independent killing of tumor cells via apoptosis, (ii) elicit a type-I interferon (IFN) response, and (iii) express high levels of the transgene. SFV vectors encoding cytokines such as interleukin (IL)-12 have shown promising therapeutic responses in experimental tumor models. Here, we developed two new recombinant SFV vectors encoding either murine tumor necrosis factor-alpha (TNF-alpha) or murine interferon-gamma (IFN-gamma), two cytokines with documented immunostimulatory and antitumor activity. The SFV vector showed high infection rate and cytotoxicity in mouse and human lung carcinoma cells in vitro. By contrast, mouse and human macrophages were resistant to infection with SFV. The recombinant SFV vectors directly inhibited mouse lung carcinoma cell growth in vitro, while exploiting the cancer cells for production of SFV vector-encoded cytokines. The functionality of SFV vector-derived TNF-alpha was confirmed through successful induction of cell death in TNF-alpha-sensitive fibroblasts in a concentration-dependent manner. SFV vector-derived IFN-gamma activated macrophages toward a tumoricidal phenotype leading to suppressed Lewis lung carcinoma cell growth in vitro in a concentration-dependent manner. The ability of SFV to provide functional cytokines and infect tumor cells but not macrophages suggests that SFV may be very useful for cancer immunotherapy employing tumor-infiltrating macrophages.

Author Info: (1) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. Cancer Gene Therapy Group, Latvian Biomedical Research and Study

Author Info: (1) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Riga, Latvia. (2) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. Department of Biosciences, University of Oslo, Oslo, Norway. (3) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. (4) Department of Laboratory Medicine, Norwegian University of Science and Technology, Trondheim, Norway. (5) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. (6) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. (7) Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital, University of Oslo, Oslo, Norway. (8) Cancer Gene Therapy Group, Latvian Biomedical Research and Study Centre, Riga, Latvia.

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Antitumor Memory T-Cells Become Functionally Mature from 30 to 100 days in a Mouse Model of Neoplasia

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Gao et al. performed a series of temporal in vivo and in vitro assays of antitumor memory T cells from immune oncotherapy-treated mice. Although mice effectively withstood rechallenge as early as 30 days after therapy, memory T cells did not maximally mature functional therapeutic efficacy or resistance to suppressor cells until 100 days after initial curative therapy. Both CD4+ and CD8+ cells were required. These results could guide vaccine strategies in which antitumor memory T cells are employed to prevent the emergence of dormant metastases.

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Gao et al. performed a series of temporal in vivo and in vitro assays of antitumor memory T cells from immune oncotherapy-treated mice. Although mice effectively withstood rechallenge as early as 30 days after therapy, memory T cells did not maximally mature functional therapeutic efficacy or resistance to suppressor cells until 100 days after initial curative therapy. Both CD4+ and CD8+ cells were required. These results could guide vaccine strategies in which antitumor memory T cells are employed to prevent the emergence of dormant metastases.

BACKGROUND: Late metastases develop from cancer of the breast, prostate, lung, kidney and malignant melanomas. Memory T-cells have excellent potential to prevent this devastating development in the same way that they routinely prevent emergence of latent viruses. MATERIAL AND METHODS: A peritoneal tumor mouse model of viral oncotherapy was used to generate therapeutic antitumor memory T-cells. Functional in vivo and in vitro assays were used to study the temporal evolution of their anticancer effects. RESULTS: Highly therapeutic antitumor memory was generated by viral oncolytic immunotherapy 30 days after treatment and matured to maximal potency at 100 days. Maturation was not uniform across different measures. CONCLUSION: The results provide guidelines for developing a viral oncolytic vaccine strategy to generate antitumor memory T-cells that can eliminate small nests of metastatic cancer cells in sanctuary sites and prevent emergence of tumors from dormant cancer cell collections. The results are relevant to any immunization strategy designed to generate antitumor memory T-cells.

Author Info: (1) Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A. (2) MMA-NMD Lab, Department of Pathology and Laboratory

Author Info: (1) Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A. (2) MMA-NMD Lab, Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, American University Hospital, Beirut, Lebanon. (3) Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A. ira.bergman@chp.edu. Department of Neurology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A. Department of Immunology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A.

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Antitumor Benefits of Antiviral Immunity: An Underappreciated Aspect of Oncolytic Virotherapies

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Oncolytic viruses (OVs) represent a new class of cancer immunotherapeutics. Administration of OVs to cancer-bearing hosts induces two distinct immunities: antiviral and antitumor. While antitumor immunity is beneficial, antiviral immune responses are often considered detrimental for the efficacy of OV-based therapy. The existing dogma postulates that anti-OV immune responses restrict viral replication and spread, and thus reduce direct OV-mediated killing of cancer cells. Accordingly, a myriad of therapeutic strategies aimed at mitigating anti-OV immune responses is presently being tested. Here, we advocate that OV-induced antiviral immune responses hold intrinsic anticancer benefits and are essential for establishing clinically desired antitumor immunity. Thus, to achieve the optimal efficacy of OV-based cancer immunotherapies, strategic management of anti-OV immune responses is of critical importance.

Author Info: (1) Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, NS, Canada; Department of Biology, Dalhousie University, NS, Canada

Author Info: (1) Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, NS, Canada; Department of Biology, Dalhousie University, NS, Canada; Centre for Innovative and Collaborative Health Sciences Research, Quality and System Performance, IWK Health Centre, Halifax, NS, Canada; These authors contributed equally to this work. (2) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Universite Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France; Universite Pierre et Marie Curie/Paris VI, Paris, France; These authors contributed equally to this work. (3) Department of Pathology, Dalhousie University, Halifax, NS, Canada. (4) Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Dalhousie University, NS, Canada; Share senior co-authorship. Electronic address: patrick.lee@dal.ca. (5) Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; INSERM, U1138, Paris, France; Equipe 11 labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Universite Paris Descartes/Paris V, Sorbonne Paris Cite, Paris, France; Universite Pierre et Marie Curie/Paris VI, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France; Pole de Biologie, Hopital Europeen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden; Share senior co-authorship. Electronic address: kroemer@orange.fr.

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