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oncolytic viruse

Ari Rosenberg, Devalingam Mahalingam
Pancreatic adenocarcinoma (PAC) remains one of the leading causes of cancer-related death. Despite multiple advances in targeted and immune therapies, the 5-year survival in advanced PAC remains poor. In this review, we discuss some of the unique aspects of the tumor microenvironment (TME) in PAC that may contribute to its resistance to immune therapies, as well as opportunities to potentially overcome some of these inherent barriers. Furthermore, we discuss strategies to enable immune therapies in PAC such as cytotoxic chemotherapy and radiation therapy, cancer vaccines, cytokine based therapy, oncolytic viruses, and adoptive T-cell therapy...
February 2018: Journal of Gastrointestinal Oncology
Jason Chesney, Yoannis Imbert-Fernandez, Sucheta Telang, Mary Baum, Smita Ranjan, Mostafa Fraig, Nicolas Batty
Talimogene laherparepvec is a genetically modified herpes simplex virus type 1-based oncolytic immunotherapy for the local treatment of unresectable subcutaneous and nodal tumors in patients with melanoma recurrent after initial surgery. We report on two patients with melanoma who, after progression on numerous systemic therapies, derived clinical benefit from talimogene laherparepvec in an expanded-access protocol (, NCT02147951). Intralesional talimogene laherparepvec (day 1, ≤4 ml 10 PFU/ml; after 3 weeks, ≤4 ml 10 PFU/ml every 2 weeks) was administered until complete response, no injectable tumors, progressive disease, or intolerance occurred...
March 21, 2018: Melanoma Research
Julia D S Hanauer, Benjamin Rengstl, Dina Kleinlützum, Johanna Reul, Anett Pfeiffer, Thorsten Friedel, Irene C Schneider, Sebastian Newrzela, Martin-Leo Hansmann, Christian J Buchholz, Alexander Muik
Classical Hodgkin lymphoma (cHL) is a hematopoietic malignancy with a characteristic cellular composition. The tumor mass is made up of infiltrated lymphocytes and other cells of hematologic origin but only very few neoplastic cells that are mainly identified by the diagnostic marker CD30. While most patients with early stage cHL can be cured by standard therapy, treatment options for relapsed or refractory cHL are still not sufficient, although immunotherapy-based approaches for the treatment of cHL patients have gained ground in the last decade...
February 27, 2018: Oncotarget
Lisa A Santry, Thomas M McAusland, Leonardo Susta, Geoffrey A Wood, Pierre P Major, Jim J Petrik, Byram W Bridle, Sarah K Wootton
Newcastle disease virus (NDV) is a single-stranded, negative-sense RNA virus in the Paramyxoviridae family. Although primarily an avian pathogen, NDV is a potent oncolytic virus that has been shown to be safe and effective in a variety of preclinical cancer models and human clinical trials. To produce virus for oncolytic trials, NDV is commonly amplified in embryonated chicken eggs and purified from the allantoic fluid. Conventional methods for purifying virus from allantoic fluid often result in relatively low-titer preparations containing high levels of impurities, including immunogenic chicken host cell proteins from allantoic fluid...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Yuki Katayama, Masashi Tachibana, Nozomi Kurisu, Yukako Oya, Yuichi Terasawa, Hiroshi Goda, Kouji Kobiyama, Ken J Ishii, Shizuo Akira, Hiroyuki Mizuguchi, Fuminori Sakurai
Oncolytic reovirus, which possesses 10 segments of dsRNA genome, mediates antitumor effects via not only virus replication in a tumor cell-specific manner, but also activation of antitumor immunity; however, the mechanism(s) of reovirus-induced activation of antitumor immunity have not been fully elucidated. Recent studies have demonstrated that overcoming an immunosuppressive environment in tumor-bearing hosts is important to achieve efficient activation of antitumor immunity. Among the various types of cells involved in immunosuppression, it has been revealed that myeloid-derived suppressor cells (MDSCs) are significantly increased in tumor-bearing hosts and play crucial roles in the immunosuppression in tumor-bearing hosts...
March 19, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Shyambabu Chaurasiya, Nanhai G Chen, Yuman Fong
Initially, direct oncolysis was thought to be the sole mechanism through which oncolytic viruses (OVs) exert their anti-tumor effect, and the immune system was perceived as the major obstacle in oncolytic virotherapy. Over the last decade, there has been a lot of debate on whether the immune system is a friend or foe of OVs. However, we are now at a stage where the initial thinking has been reversed as a result of compelling evidence that the immune system plays a critical role in the success of oncolytic virotherapy...
March 15, 2018: Current Opinion in Immunology
Matthew J Atherton, Kyle B Stephenson, Jake K Nikota, Qian N Hu, Andrew Nguyen, Yonghong Wan, Brian D Lichty
Human papilloma virus (HPV)-associated cancer is a significant global health burden and despite the presence of viral transforming antigens within neoplastic cells, therapeutic vaccinations are ineffective for advanced disease. HPV positive TC1 cells are susceptible to viral oncolysis by MG1-E6E7, a custom designed oncolytic Maraba virus. Epitope mapping of mice vaccinated with MG1-E6E7 enabled the rational design of synthetic long peptide (SLP) vaccines against HPV16 and HPV18 antigens. SLPs were able to induce specific CD8+ immune responses and the magnitude of these responses significantly increased when boosted by MG1-E6E7...
March 12, 2018: Vaccine
Leslee Sprague, Joel M Lee, Brian J Hutzen, Pin-Yi Wang, Chun-Yu Chen, Joe Conner, Lynne Braidwood, Kevin A Cassady, Timothy P Cripe
High Mobility Group Box 1 (HMGB1) is a multifunctional protein that plays various roles in the processes of inflammation, cancer, and other diseases. Many reports document abundant HMGB1 release following infection with oncolytic viruses (OVs). Further, other groups including previous reports from our laboratory highlight the synergistic effects of OVs with chemotherapy drugs. Here, we show that virus-free supernatants have varying cytotoxic potential, and HMGB1 is actively secreted by two established fibroblast cell lines (NIH 3T3 and 3T6-Swiss albino) following HSV1716 infection in vitro...
March 15, 2018: Viruses
Cun-Zhi Lin, Gui-Ling Xiang, Xin-Hong Zhu, Lu-Lu Xiu, Jia-Xing Sun, Xiao-Yuan Zhang
Cancer virotherapy mediated by oncolytic viruses (OV), has emerged as a novel and effective strategy in cancer therapeutics. Preclinical models have demonstrated anticancer activity against numerous types of cancer. Currently, a number of recombinant viruses are in late phase clinical trials, many of which have demonstrated promising results regarding the safety and reliability of the treatments, particularly when combined with standard antineoplastic therapies. In addition to molecular-targeted therapeutics, genetic engineering of the viruses allows functional complementation to chemotherapy or radiotherapy agents...
April 2018: Oncology Letters
S N Shchelkunov, I A Razumov, I V Kolosova, A V Romashchenko, E L Zavjalov
The possibility of glioblastoma virotherapy at intravenous injection of the LIVP-GFP recombinant virus was studied in experimental model of orthotopic xenotransplantation of human glioblastoma cell line U87 to SCID laboratory mice. The LIVP-GFP recombinant virus deficient for thymidine kinase exhibited a significantly greater oncolytic capacity than the original LIVP virus, and an intravenous injection of LIVP-GFP at the early stages of tumorigenesis in mouse brain in most cases resulted in the lysis of the tumor...
January 2018: Doklady. Biochemistry and Biophysics
Guna Proboka, Andra Tilgase, Sergejs Isajevs, Agnija Rasa, Pēteris Alberts
Melanoma is considered an aggressive malignancy with a tendency of forming metastasis in the brain. Less than 10% of all melanoma cases present with unknown primary tumor location. This diagnose is yet to be fully understood, because there are only theoretical assumptions about the nature of the disease. Melanoma brain metastases have many severe side effects and, unfortunately, any disease related to the brain has limited therapeutic options due to the blood-brain barrier. The course of the disease after a treatment course is complicated to predict, and it is difficult to obtain long-lasting remission...
2018: Frontiers in Oncology
Jovan Nikolic, Laura Belot, Hélène Raux, Pierre Legrand, Yves Gaudin, Aurélie A Albertini
Vesicular stomatitis virus (VSV) is an oncolytic rhabdovirus and its glycoprotein G is widely used to pseudotype other viruses for gene therapy. Low-density lipoprotein receptor (LDL-R) serves as a major entry receptor for VSV. Here we report two crystal structures of VSV G in complex with two distinct cysteine-rich domains (CR2 and CR3) of LDL-R, showing that their binding sites on G are identical. We identify two basic residues on G, which are essential for its interaction with CR2 and CR3. Mutating these residues abolishes VSV infectivity even though VSV can use alternative receptors, indicating that all VSV receptors are members of the LDL-R family...
March 12, 2018: Nature Communications
Hiroshi Nakashima, Tran Nguyen, Kazue Kasai, Carmela Passaro, Hirotaka Ito, William F Goins, Imran Shaikh, Ronald Erdelyi, Reiko Nishihara, Ichiro Nakano, David A Reardon, Ana C Anderson, Vijay Kuchroo, E Antonio Chiocca
PURPOSE: Glioblastoma (GBM) is the most common primary central nervous system cancer in adults. Oncolytic HSV-1 (oHSV) is the first FDA-approved gene therapy approach for the treatment of malignant melanoma. For GBM, oHSVs need to be engineered to replicate within and be toxic to the glial tumor but not to normal brain parenchymal cells. We have thus engineered a novel oHSV to achieve these objectives. EXPERIMENTAL DESIGN: NG34 is an attenuated HSV-1 with deletions in the genes encoding viral ICP6 and ICP34...
March 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Dmitriy Zamarin, Jacob M Ricca, Svetlana Sadekova, Anton Oseledchyk, Ying Yu, Wendy M Blumenschein, Jerelyn Wong, Mathieu Gigoux, Taha Merghoub, Jedd D Wolchok
Intralesional therapy with oncolytic viruses (OVs) leads to the activation of local and systemic immune pathways, which may present targets for further combinatorial therapies. Here, we used human tumor histocultures as well as syngeneic tumor models treated with Newcastle disease virus (NDV) to identify a range of immune targets upregulated with OV treatment. Despite tumor infiltration of effector T lymphocytes in response to NDV, there was ongoing inhibition through programmed death ligand 1 (PD-L1), acting as a mechanism of early and late adaptive immune resistance to the type I IFN response and T cell infiltration, respectively...
March 5, 2018: Journal of Clinical Investigation
Praveen K Bommareddy, Howard L Kaufman
Oncolytic viruses (OVs) are a versatile new class of therapeutic agents based on native or genetically modified viruses that selectively replicate in tumor cells and can express therapeutic transgenes designed to target cells within the tumor microenvironment and/or host immunity. To date, however, confirmation of the underlying mechanism of action and an understanding of innate and acquired drug resistance for most OVs have been limited. In this issue of the JCI, Zamarin et al. report a comprehensive analysis of an oncolytic Newcastle disease virus (NDV) using both murine melanoma tumor models and human tumor explants to explore how the virus promotes tumor eradication and details of the mechanisms involved...
March 5, 2018: Journal of Clinical Investigation
Janine Kimpel, Carles Urbiola, Iris Koske, Reinhard Tober, Zoltan Banki, Guido Wollmann, Dorothee von Laer
Previously, we described VSV-GP, a modified version of the vesicular stomatitis virus, as a non-neurotoxic oncolytic virus that is effective for the treatment of malignant glioblastoma and ovarian cancer. Here, we evaluate the therapeutic efficacy of VSV-GP for malignant melanoma. All of the human, mouse, and canine melanoma cell lines that were tested, alongside most primary human melanoma cultures, were infected by VSV-GP and efficiently killed. Additionally, we found that VSV-GP prolonged the survival of mice in both a xenograft and a syngeneic mouse model...
March 2, 2018: Viruses
Iliana Georgana, Rebecca P Sumner, Greg J Towers, Carlos Maluquer de Motes
Cytosolic recognition of DNA has emerged as a critical cellular mechanism of host immune activation upon pathogen invasion. The central cytosolic DNA sensor cGAS activates STING, which is phosphorylated, dimerises and translocates from the ER to a perinuclear region to mediate IRF-3 activation. Poxviruses are dsDNA viruses replicating in the cytosol and hence likely to trigger cytosolic DNA sensing. Here we investigated the activation of innate immune signalling by 4 different strains of the prototypic poxvirus vaccinia virus (VACV) in a cell line proficient in DNA sensing...
February 28, 2018: Journal of Virology
Bernhard Josef Eigl, Kim Chi, Dongsheng Tu, Sebastien J Hotte, Eric Winquist, Christopher M Booth, Christina Canil, Kylea Potvin, Richard Gregg, Scott North, Muhammad Zulfiqar, Susan Ellard, Joseph Dean Ruether, Lyly Le, A Saranya Kakumanu, Mohammad Salim, Alison L Allan, Harriet Feilotter, Ashley Theis, Lesley Seymour
Background: Pelareorep is an oncolytic virus with activity in many cancers including prostate. It has in vitro synergism with microtubule-targeted agents. We undertook a clinical trial evaluating pelareorep in mCRPC patients receiving docetaxel. Patients and Methods: In this randomized, open-label phase II study, patients received docetaxel 75mg/m2 on day 1 of a 21-day cycle and prednisone 5mg twice daily, in combination with pelareorep (arm A) or alone (arm B)...
January 30, 2018: Oncotarget
Ho Anh Son, LiFeng Zhang, Bui Khac Cuong, Hoang Van Tong, Le Duy Cuong, Ngo Thu Hang, Hoang Thi My Nhung, Naoki Yamamoto, Nguyen Linh Toan
Oncolytic measles and mumps viruses (MeV, MuV) have a potential for anti-cancer treatment. We examined the anti-tumor activity of MeV, MuV, and MeV-MuV combination (MM) against human solid malignancies (HSM). MeV, MuV, and MM targeted and significantly killed various cancer cell lines of HSM but not normal cells. MM demonstrated a greater anti-tumor effect and prolonged survival in a human prostate cancer xenograft tumor model compared to MeV and MuV. MeV, MuV, and MM significantly induced the expression of immunogenic cell death markers and enhanced spleen-infiltrating immune cells...
February 27, 2018: Cancer Investigation
Jacob M Ricca, Anton Oseledchyk, Tyler Walther, Cailian Liu, Levi Mangarin, Taha Merghoub, Jedd D Wolchok, Dmitriy Zamarin
Anti-viral immunity presents a major hurdle for systemically administered oncolytic viruses (OV). Intratumoral OV therapy has a potential to overcome this problem through activation of anti-tumor immune response, with local and abscopal effects. However, the effects of anti-viral immunity in such a setting are still not well defined. Using Newcastle Disease Virus (NDV) as a model, we explore the effects of pre-existing anti-viral immunity on therapeutic efficacy in syngeneic mouse tumor models. Unexpectedly, we find that while pre-existing immunity to NDV limits its replication in tumors, tumor clearance, abscopal anti-tumor immune effects, and survival are not compromised and, on the contrary, are superior in NDV-immunized mice...
January 31, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
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